Activin A, a Novel Chemokine, Induces Mouse NK Cell Migration via AKT and Calcium Signaling.

Natural killer (NK) cells can migrate quickly to the tumor site to exert cytotoxic effects on tumors, and some chemokines, including CXCL8, CXCL10 or and CXCL12, can regulate the migration of NK cells. Activin A, a member of the transforming growth factor ß (TGF-ß) superfamily, is highly expressed in tumor tissues and involved in tumor development and immune cell activation. In this study, we focus on the effects of activin A on NK cell migration. In vitro, activin A induced NK cell migration and invasion, promoted cell polarization and inhibited cell adhesion. Moreover, activin A increased Ca2+, p-SMAD3 and p-AKT levels in NK cells. An AKT inhibitor and Ca2+ chelator partially blocked activin A-induced NK cell migration. In vivo, exogenous activin A increased tumor-infiltrating NK cells in NS-1 cell solid tumors and inhibited tumor growth, and blocking endogenous activin A with anti-activin A antibody reduced tumor-infiltrating NK cells in 4T-1 cell solid tumors. These results suggest that activin A induces NK cell migration through AKT signaling and calcium signaling and may enhance the antitumor effect of NK cells by increasing tumor-infiltrating NK cells.

Analysis of Predictive Information From Biomarkers Added to Clinical Models of Preeclampsia: Consideration of PAPP-A2, Activin A, and sFlt-1:PlGF Ratio.

BACKGROUND: Preeclampsia remains a major cause of maternal and fetal adverse outcomes in pregnancy; however, accurate and universally acceptable predictive tools remain elusive. We investigated whether a panel of biomarkers could improve risk prediction for preeclampsia when measured at various pregnancy time points. METHODS: In this prospective cohort study, 192 women with first-trimester high-risk singleton pregnancies were consecutively recruited from tertiary obstetrics clinics in Montréal, Canada. Clinical information (height, pre-pregnancy weight, personal and family medical history, medication use) was collected at baseline. Blood pressure was measured and blood samples collected at each trimester to quantify soluble Fms-like tyrosine kinase 1 (sFlt-1), placental growth factor (PlGF), pregnancy-associated plasma protein A2 (PAPP-A2), PAPP-A, activin A, inhibin A, follistatin, and glycosylated fibronectin. A random-effects hierarchic logistic regression model was used to relate change in biomarker levels to incidence of preeclampsia. RESULTS: When added to a clinical model composed of maternal age, pre-pregnancy body mass index, race, and mean arterial pressure, a positive third-trimester result for both PAPP-A2 and activin A had a better positive predictive value than the sFlt-1:PlGF ratio added to the clinical model (91.67% [95% confidence interval (CI) 78.57%-100%] vs 66.67% [57.14%-100%]), while maintaining a comparable high negative predictive value (97.69% [95% CI 95.34%-100%] vs 96.00% [92.19%-99.21%]). CONCLUSIONS: Whereas the third-trimester sFlt-1:PlGF ratio can predict short-term absence of preeclampsia, PAPP-A2 and activin A had both high positive and negative predictive values and therefore could serve as biomarkers to predict the occurrence (and absence) of preeclampsia; these findings will be validated in future studies.

Gonadotropin elevation is ootoxic to ovulatory oocytes and inhibits oocyte maturation, and activin decoy receptor ActRIIB:Fc therapeutically restores maturation.

BACKGROUND: Elevated FSH often occurs in women of advanced maternal age (AMA, age ≥ 35) and in infertility patients undergoing controlled ovarian stimulation (COS). There is controversy on whether high endogenous FSH contributes to infertility and whether high exogenous FSH adversely impacts patient pregnancy rates. METHODS: The senescence-accelerated mouse-prone-8 (SAMP8) model of female reproductive aging was employed to assess the separate impacts of age and high FSH activity on the percentages (%) of viable and mature ovulated oocytes recovered after gonadotropin treatment. Young and midlife mice were treated with the FSH analog equine chorionic gonadotropin (eCG) to model both endogenous FSH elevation and exogenous FSH elevation. Previously we showed the activin inhibitor ActRIIB:Fc increases oocyte quality by preventing chromosome and spindle misalignments. Therefore, ActRIIB:Fc treatment was performed in an effort to increase % oocyte viability and % oocyte maturation. RESULTS: The high FSH activity of eCG is ootoxic to ovulatory oocytes, with greater decreases in % viable oocytes in midlife than young mice. High FSH activity of eCG potently inhibits oocyte maturation, decreasing the % of mature oocytes to similar degrees in young and midlife mice. ActRIIB:Fc treatment does not prevent eCG ootoxicity, but it restores most oocyte maturation impeded by eCG. CONCLUSIONS: FSH ootoxicity to ovulatory oocytes and FSH maturation inhibition pose a paradox given the well-known pro-growth and pro-maturation activities of FSH in the earlier stages of oocyte growth. We propose the FOOT Hypothesis ("FSH OoToxicity Hypothesis), that FSH ootoxicity to ovulatory oocytes comprises a new driver of infertility and low pregnancy success rates in DOR women attempting spontaneous pregnancy and in COS/IUI patients, especially AMA women. We speculate that endogenous FSH elevation also contributes to reduced fecundity in these DOR and COS/IUI patients. Restoration of oocyte maturation by ActRIB:Fc suggests that activin suppresses oocyte maturation in vivo. This contrasts with prior studies showing activin A promotes oocyte maturation in vitro. Improved oocyte maturation with agents that decrease endogenous activin activity with high specificity may have therapeutic benefit for COS/IVF patients, COS/IUI patients, and DOR patients attempting spontaneous pregnancies.

Low concentrations of saracatinib promote definitive endoderm differentiation through inhibition of FAK-YAP signaling axis.

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.

Gene Function is a Driver of Activin Signaling Pathway Evolution Following Whole-Genome Duplication in Rainbow Trout (Oncorhynchus mykiss).

The genomes of plant and animal species are influenced by ancestral whole-genome duplication (WGD) events, which have profound impacts on the regulation and function of gene networks. To gain insight into the consequences of WGD events, we characterized the sequence conservation and expression patterns of ohnologs in the highly duplicated activin receptor signaling pathway in rainbow trout (RBT). The RBT activin receptor signaling pathway is defined by tissue-specific expression of inhibitors and ligands and broad expression of receptors and Co-Smad signaling molecules. Signaling pathway ligands exhibited shared expression, while inhibitors and Smad signaling molecules primarily express a single dominant ohnolog. Our findings suggest that gene function influences ohnolog evolution following duplication of the activin signaling pathway in RBT.

ARID1B maintains mesenchymal stem cell quiescence via inhibition of BCL11B-mediated non-canonical Activin signaling.

ARID1B haploinsufficiency in humans causes Coffin-Siris syndrome, associated with developmental delay, facial dysmorphism, and intellectual disability. The role of ARID1B has been widely studied in neuronal development, but whether it also regulates stem cells remains unknown. Here, we employ scRNA-seq and scATAC-seq to dissect the regulatory functions and mechanisms of ARID1B within mesenchymal stem cells (MSCs) using the mouse incisor model. We reveal that loss of Arid1b in the GLI1+ MSC lineage disturbs MSCs' quiescence and leads to their proliferation due to the ectopic activation of non-canonical Activin signaling via p-ERK. Furthermore, loss of Arid1b upregulates Bcl11b, which encodes a BAF complex subunit that modulates non-canonical Activin signaling by directly regulating the expression of activin A subunit, Inhba. Reduction of Bcl11b or non-canonical Activin signaling restores the MSC population in Arid1b mutant mice. Notably, we have identified that ARID1B suppresses Bcl11b expression via specific binding to its third intron, unveiling the direct inter-regulatory interactions among BAF subunits in MSCs. Our results demonstrate the vital role of ARID1B as an epigenetic modifier in maintaining MSC homeostasis and reveal its intricate mechanistic regulatory network in vivo, providing novel insights into the linkage between chromatin remodeling and stem cell fate determination.

Involvement of somatotrophic hormones in the postpartum regulation of ovarian activity in mares.

Mares resume ovarian activity rapidly after foaling. Besides follicle-stimulating hormone (FSH) and luteinizing hormone (LH), the pituitary synthesizes prolactin and growth hormone which stimulate insulin-like growth factor (IGF) synthesis in the liver. We tested the hypothesis that follicular growth is initiated already antepartum, mares with early and delayed ovulation differ in IGF-1 release and that there is an additional IGF-1 synthesis in the placenta. Plasma concentrations of LH, FSH, IGF-1, IGF-2, activin and prolactin. IGF-1, IGF-2, prolactin and their receptors in placental tissues were analyzed at the mRNA and protein level. Follicular growth was determined from 15 days before to 15 days after foaling in 14 pregnancies. Mares ovulating within 15 days postpartum formed group OV (n=5) and mares not ovulating within 15 days group NOV (n=9). Before foaling, follicles with a diameter >1 cm were present in all mares and their number increased over time (p<0.05). Follicle growth after foaling was more pronounced in OV mares (day p<0.001, group p<0.05, day x group p<0.05) in parallel to an increase in LH concentration (p<0.001, day x group p<0.001) while FSH increased (p<0.001) similarly in both groups. Plasma concentrations of IGF-1 and prolactin peaked one day after foaling (p<0.001). The IGF-1 mRNA abundance was higher in the allantochorion but lower in the amnion of OV versus NOV mares (group p=0.01, localization x group p<0.01). The IGF-1 receptor mRNA was most abundant in the allantochorion (p<0.001) and IGF-1 protein was expressed in placental tissue without differences between groups. In conclusion, follicular growth in mares is initiated before foaling and placental IGF-1 may enhance resumption of ovulatory cycles.

ID1high/activin Ahigh glioblastoma cells contribute to resistance to anti-angiogenesis therapy through malformed vasculature.

Although bevacizumab (BVZ), a representative drug for anti-angiogenesis therapy (AAT), is used as a first-line treatment for patients with glioblastoma (GBM), its efficacy is notably limited. Whereas several mechanisms have been proposed to explain the acquisition of AAT resistance, the specific underlying mechanisms have yet to be sufficiently ascertained. Here, we established that inhibitor of differentiation 1 (ID1)high/activin Ahigh glioblastoma cell confers resistance to BVZ. The bipotent effect of activin A during its active phase was demonstrated to reduce vasculature dependence in tumorigenesis. In response to a temporary exposure to activin A, this cytokine was found to induce endothelial-to-mesenchymal transition via the Smad3/Slug axis, whereas prolonged exposure led to endothelial apoptosis. ID1 tumors showing resistance to BVZ were established to be characterized by a hypovascular structure, hyperpermeability, and scattered hypoxic regions. Using a GBM mouse model, we demonstrated that AAT resistance can be overcome by administering therapy based on a combination of BVZ and SB431542, a Smad2/3 inhibitor, which contributed to enhancing survival. These findings offer valuable insights that could contribute to the development of new strategies for treating AAT-resistant GBM.

Subtype and Lineage-Mediated Protocol for Standardizing Activin/Nodal and BMP Signaling for hiPSC-Derived Cardiomyocyte Differentiation.

The adept and systematic differentiation of embryonic stem cells (ESCs) and human-induced pluripotent stem cells (hiPSCs) to diverse lineage-prone cell types involves crucial step-by-step process that mimics the vital strategic commitment phase that is usually observed during the process of embryo development. The development of precise tissue-specific cell types from these stem cells indeed plays an important role in the advancement of imminent stem cell-based therapeutic strategies. Therefore, the usage of hiPSC-derived cell types for subsequent cardiovascular disease modeling, drug screening, and therapeutic drug development undeniably entails an in-depth understanding of each and every step to proficiently stimulate these stem cells into desired cardiomyogenic lineage. Thus, to accomplish this definitive and decisive fate, it is essential to efficiently induce the mesoderm or pre-cardiac mesoderm, succeeded by the division of cells into cardiovascular and ultimately ensuing with the cardiomyogenic lineage outcome. This usually commences from the earliest phases of pluripotent cell induction. In this chapter, we discuss our robust and reproducible step-wise protocol that will describe the subtype controlled, precise lineage targeted standardization of activin/nodal, and BMP signaling molecules/cytokines, for the efficient differentiation of ventricular cardiomyocytes from hiPSCs via the embryoid body method. In addition, we also describe techniques to dissociate hiPSCs, hiPSC-derived early cardiomyocytes for mesoderm and pre-cardiac mesoderm assessment, and hiPSC-derived cardiomyocytes for early and mature markers assessment.

Activin A signaling stimulates neutrophil activation and macrophage migration in pancreatitis.

Acute Pancreatitis (AP) is associated with high mortality and current treatment options are limited to supportive care. We found that blockade of activin A (activin) in mice improves outcomes in two murine models of AP. To test the hypothesis that activin is produced early in response to pancreatitis and is maintained throughout disease progression to stimulate immune cells, we first performed digital spatial profiling (DSP) of human chronic pancreatitis (CP) patient tissue. Then, transwell migration assays using RAW264.7 mouse macrophages and qPCR analysis of "neutrophil-like" HL-60 cells were used for functional correlation. Immunofluorescence and western blots on cerulein-induced pancreatitis samples from pancreatic acinar cell-specific Kras knock-in (Ptf1aCreER™; LSL-KrasG12D) and functional WT Ptf1aCreER™ mouse lines mimicking AP and CP to allow for in vivo confirmation. Our data suggest activin promotes neutrophil and macrophage activation both in situ and in vitro, while pancreatic activin production is increased as early as 1 h in response to pancreatitis and is maintained throughout CP in vivo. Taken together, activin is produced early in response to pancreatitis and is maintained throughout disease progression to promote neutrophil and macrophage activation.

Antagonizing Activin A/p15INK4b Signaling as Therapeutic Strategy for Liver Disease.

BACKGROUND/AIM: Activin A is involved in the pathogenesis of human liver diseases, but its therapeutic targeting is not fully explored. Here, we tested the effect of novel, highly specific small-molecule-based activin A antagonists (NUCC-474/555) in improving liver regeneration following partial hepatectomy and halting fibrosis progression in models of chronic liver diseases (CLDs). METHODS: Cell toxicity of antagonists was determined in rat hepatocytes and Huh-7 cells using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide assay. Hepatocytes and hepatic stellate cells (HSCs) were treated with activin A and NUCC-555 and analyzed by reverse transcription-polymerase chain reaction and immunohistochemistry. Partial hepatectomized Fisher (F)344 rats were treated with NUCC-555, and bromodeoxyuridine (BrdU) incorporation was determined at 18/24/36/120/240 h. NUCC-555 was administered into thioacetamide- or carbon tetrachloride-treated F344 rats or C57BL/6 mice, and the fibrosis progression was studied. RESULTS: NUCC-474 showed higher cytotoxicity in cultured hepatic cells; therefore, NUCC-555 was used in subsequent studies. Activin A-stimulated overexpression of cell cycle-/senescence-related genes (e.g., p15INK4b, DEC1, Glb1) was near-completely reversed by NUCC-555 in hepatocytes. Activin A-mediated HSC activation was blocked by NUCC-555. In partial hepatectomized rats, antagonizing activin A signaling resulted in a 1.9-fold and 2.3-fold increase in BrdU+ cells at 18 and 24 h, respectively. Administration of NUCC-555 in rats and mice with progressing fibrosis significantly reduced collagen accumulation (7.9-fold), HSC activation indicated by reduced alpha smooth muscle actin+ and vimentin+ cells, and serum aminotransferase activity. CONCLUSIONS: Our studies demonstrate that activin A antagonist NUCC-555 promotes liver regeneration and halts fibrosis progression in CLD models, suggesting that blocking activin A signaling may represent a new approach to treating people with CLD.

Activin A levels in metabolic dysfunction-associated steatotic liver disease associates with fibrosis and the PNPLA3 I148M variant.

BACKGROUND: Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most prevalent chronic liver condition worldwide. There is an urgent need to develop new biomarkers to assess disease severity and to define patients with a progressive phenotype. Activin A is a new promising biomarker with conflicting results about liver fibrosis. In this study we investigate levels of Activin A in patients with biopsy proven MASLD. We assess levels of Activin A in regard to fibrosis stage and genetic variant I148M in the patatin-like phospholipase domain-containing protein 3 (PNPLA3). METHODS: Activin A levels were assessed in plasma samples from patients with biopsy-proven MASLD in a cross-sectional study. All patients were clinically evaluated and the PNPLA3 I148M genotype of the cohort was assessed. FINDINGS: 41 patients were included and 27% of these had advanced fibrosis. In MASLD patients with advanced fibrosis, Activin A levels was higher (p < 0.001) and could classify advanced fibrosis with an AUROC for activin A of 0.836 (p < 0.001). Patients homozygous for PNPLA3 I148M G/G had higher levels of activin A than non-homozygotes (p = 0.027). CONCLUSIONS: Circulating activin A levels were associated with advanced fibrosis and could be a potential blood biomarker for identifying advanced fibrosis in MASLD. Patients with the risk genotype PNPLA3 I148M G/G had higher levels of activin A proposing activin A as a contributor of the transition from simple steatosis to a fibrotic phenotype.

Reactivation of herpesvirus type 6 and IgA/IgM-mediated responses to activin-A underpin long COVID, including affective symptoms and chronic fatigue syndrome.

BACKGROUND: Persistent infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), reactivation of dormant viruses, and immune-oxidative responses are involved in long COVID. OBJECTIVES: To investigate whether long COVID and depressive, anxiety, and chronic fatigue syndrome (CFS) symptoms are associated with IgA/IgM/IgG to SARS-CoV-2, human herpesvirus type 6 (HHV-6), Epstein-Barr Virus (EBV), and immune-oxidative biomarkers. METHODS: We examined 90 long COVID patients and ninety healthy controls. We measured serum IgA/IgM/IgG against HHV-6 and EBV and their deoxyuridine 5'-triphosphate nucleotidohydrolase (duTPase), SARS-CoV-2, and activin-A, C-reactive protein (CRP), advanced oxidation protein products (AOPP), and insulin resistance (HOMA2-IR). RESULTS: Long COVID patients showed significant elevations in IgG/IgM-SARS-CoV-2, IgG/IgM-HHV-6, and HHV-6-duTPase, IgA/IgM-activin-A, CRP, AOPP, and HOMA2-IR. Neural network analysis yielded a highly significant predictive accuracy of 80.6% for the long COVID diagnosis (sensitivity: 78.9%, specificity: 81.8%, area under the ROC curve = 0.876); the topmost predictors were as follows: IGA-activin-A, IgG-HHV-6, IgM-HHV-6-duTPase, IgG-SARS-CoV-2, and IgM-HHV-6 (all positively) and a factor extracted from all IgA levels to all viral antigens (inversely). The top 5 predictors of affective symptoms due to long COVID were IgM-HHV-6-duTPase, IgG-HHV-6, CRP, education, IgA-activin-A (predictive accuracy of r = 0.636). The top 5 predictors of CFS due to long COVID were in descending order: CRP, IgG-HHV-6-duTPase, IgM-activin-A, IgM-SARS-CoV-2, and IgA-activin-A (predictive accuracy: r = 0.709). CONCLUSION: Reactivation of HHV-6, SARS-CoV-2 persistence, and autoimmune reactions to activin-A combined with activated immune-oxidative pathways play a major role in the pathophysiology of long COVID as well as the severity of its affective symptoms and CFS.

Myostatin and Activin A as Biomarkers of Sarcopenia in Inflammatory Bowel Disease Patients.

The prevalence of sarcopenia in inflammatory bowel disease patients has received increasing attention. The aim of this study is to assess the usefulness of determining levels of myostatin (MSTN) and activin A (Act A) as potential markers of disease activity and occurrence of sarcopenia in Crohn's disease and ulcerative colitis patients. The case-control study included 82 patients with Inflammatory Bowel Disease. The control group consisted of 25 healthy volunteers. The serum levels of myostatin and activin A were determined by the quantitative sandwich enzyme-linked immunosorbent assay. Sarcopenia was diagnosed based on the EWGSOP2 criteria. The study found lower levels of myostatin and activin A in the IBD patients. There were significantly lower levels of myostatin (80.6 pg/mL vs. 186.2 pg/mL; p = 0.0364) as well as activin A (32.1 pg/mL vs. 35.2 pg/mL; p = 0.0132) in the IBD patients with sarcopenia compared to those without sarcopenia. Positive correlations were found between MSTN levels and Muscle Mass Index (rho = 0.31; p < 0.005) and hand grip strength (rho = 0.34, p < 0.05) in the IBD patients. The determination of serum levels of MSTN and Act A may be useful in the early diagnosis of sarcopenia in IBD patients.

Neutrophil-derived Activin-A moderates their pro-NETotic activity and attenuates collateral tissue damage caused by Influenza A virus infection.

Background: Pre-neutrophils, while developing in the bone marrow, transcribe the Inhba gene and synthesize Activin-A protein, which they store and release at the earliest stage of their activation in the periphery. However, the role of neutrophil-derived Activin-A is not completely understood. Methods: To address this issue, we developed a neutrophil-specific Activin-A-deficient animal model (S100a8-Cre/Inhba fl/fl mice) and analyzed the immune response to Influenza A virus (IAV) infection. More specifically, evaluation of body weight and lung mechanics, molecular and cellular analyses of bronchoalveolar lavage fluids, flow cytometry and cell sorting of lung cells, as well as histopathological analysis of lung tissues, were performed in PBS-treated and IAV-infected transgenic animals. Results: We found that neutrophil-specific Activin-A deficiency led to exacerbated pulmonary inflammation and widespread hemorrhagic histopathology in the lungs of IAV-infected animals that was associated with an exuberant production of neutrophil extracellular traps (NETs). Moreover, deletion of the Activin-A receptor ALK4/ACVR1B in neutrophils exacerbated IAV-induced pathology as well, suggesting that neutrophils themselves are potential targets of Activin-A-mediated signaling. The pro-NETotic tendency of Activin-A-deficient neutrophils was further verified in the context of thioglycollate-induced peritonitis, a model characterized by robust peritoneal neutrophilia. Of importance, transcriptome analysis of Activin-A-deficient neutrophils revealed alterations consistent with a predisposition for NET release. Conclusion: Collectively, our data demonstrate that Activin-A, secreted by neutrophils upon their activation in the periphery, acts as a feedback mechanism to moderate their pro-NETotic tendency and limit the collateral tissue damage caused by neutrophil excess activation during the inflammatory response.

Activin E is a transforming growth factor ß ligand that signals specifically through activin receptor-like kinase 7.

Activins are one of the three distinct subclasses within the greater Transforming growth factor ß (TGFß) superfamily. First discovered for their critical roles in reproductive biology, activins have since been shown to alter cellular differentiation and proliferation. At present, members of the activin subclass include activin A (ActA), ActB, ActC, ActE, and the more distant members myostatin and GDF11. While the biological roles and signaling mechanisms of most activins class members have been well-studied, the signaling potential of ActE has remained largely unknown. Here, we characterized the signaling capacity of homodimeric ActE. Molecular modeling of the ligand:receptor complexes showed that ActC and ActE shared high similarity in both the type I and type II receptor binding epitopes. ActE signaled specifically through ALK7, utilized the canonical activin type II receptors, ActRIIA and ActRIIB, and was resistant to the extracellular antagonists follistatin and WFIKKN. In mature murine adipocytes, ActE invoked a SMAD2/3 response via ALK7, like ActC. Collectively, our results establish ActE as a specific signaling ligand which activates the type I receptor, ALK7.

In chronic kidney disease altered cardiac metabolism precedes cardiac hypertrophy.

Conduit arterial disease in chronic kidney disease (CKD) is an important cause of cardiac complications. Cardiac function in CKD has not been studied in the absence of arterial disease. In an Alport syndrome model bred not to have conduit arterial disease, mice at 225 days of life (dol) had CKD equivalent to humans with CKD stage 4-5. Parathyroid hormone (PTH) and FGF23 levels were one log order elevated, circulating sclerostin was elevated, and renal activin A was strongly induced. Aortic Ca levels were not increased, and vascular smooth muscle cell (VSMC) transdifferentiation was absent. The CKD mice were not hypertensive, and cardiac hypertrophy was absent. Freshly excised cardiac tissue respirometry (Oroboros) showed that ADP-stimulated O2 flux was diminished from 52 to 22 pmol/mg (P = 0.022). RNA-Seq of cardiac tissue from CKD mice revealed significantly decreased levels of cardiac mitochondrial oxidative phosphorylation genes. To examine the effect of activin A signaling, some Alport mice were treated with a monoclonal Ab to activin A or an isotype-matched IgG beginning at 75 days of life until euthanasia. Treatment with the activin A antibody (Ab) did not affect cardiac oxidative phosphorylation. However, the activin A antibody was active in the skeleton, disrupting the effect of CKD to stimulate osteoclast number, eroded surfaces, and the stimulation of osteoclast-driven remodeling. The data reported here show that cardiac mitochondrial respiration is impaired in CKD in the absence of conduit arterial disease. This is the first report of the direct effect of CKD on cardiac respiration.NEW & NOTEWORTHY Heart disease is an important morbidity of chronic kidney disease (CKD). Hypertension, vascular stiffness, and vascular calcification all contribute to cardiac pathophysiology. However, cardiac function in CKD devoid of vascular disease has not been studied. Here, in an animal model of human CKD without conduit arterial disease, we analyze cardiac respiration and discover that CKD directly impairs cardiac mitochondrial function by decreasing oxidative phosphorylation. Protection of cardiac oxidative phosphorylation may be a therapeutic target in CKD.

Expression of SMADs in orthotopic human endometrium, ovarian endometriosis, and endometriotic lesions in a murine model.

Activin A promotes the development of endometriotic lesions in a murine model of endometriosis, and the immunohistochemical localization of phosphorylated suppressor of mothers against decapentaplegic homolog 2/3 (pSMAD2/3) complex in endometriotic lesions has been reported. Activin may therefore be involved in the development and proliferation of endometriotic cells via the SMAD signaling pathway. However, few detailed reports exist on SMAD7 expression in endometriosis. The purpose of this study was to investigate the expression of pSMAD2/3 or pSMAD3 and SMAD7 in the orthotopic human endometrium, ovarian endometriosis, and endometriotic lesions in a murine model and the effect of activin A on pSMAD2/3 and SMAD7 expression. We established an endometriosis murine model via the intraperitoneal administration of endometrial tissue and blood from donor mice. Activin A was intraperitoneally administered to the activin group. We immunohistochemically evaluated orthotopic endometria, ovarian endometriotic tissues, and endometriotic lesions in the murine model followed by western blotting. We found that pSMAD3 and SMAD7 were expressed in ovarian endometriosis and orthotopic endometria from patients with and without endometriosis. In the murine model, endometriotic lesions expressed pSMAD2/3 and SMAD7 in the activin and control groups, and higher SMAD7 expression was found in the activin group. To the best of our knowledge, this study is the first to show that SMAD7 expression is upregulated in endometriosis. In conclusion, these results suggest that activin A activates the SMAD signaling pathway and promotes the development of endometriotic lesions, thus identifying SMAD7 as a potential therapeutic target for endometriosis.

Activin receptors in human cancer: Functions, mechanisms, and potential clinical applications.

Activins are members of the transforming growth factor-ß (TGF-ß) superfamily and act as key regulators in various physiological processes, such as follicle and embryonic development, as well as in multiple human diseases, including cancer. They have been established to signal through three type I and two type II serine/threonine kinase receptors, which, upon ligand binding, form a final signal-transducing receptor complex that activates downstream signaling and governs gene expression. Recent research highlighted the dysregulation of the expression or activity of activin receptors in multiple human cancers and their critical involvement in cancer progression. Furthermore, expression levels of activin receptors have been associated with clinicopathological features and patient outcomes across different cancers. However, there is currently a paucity of comprehensive systematic reviews of activin receptors in cancer. Thus, this review aimed to consolidate existing knowledge concerning activin receptors, with a primary emphasis on their signaling cascade and emerging biological functions, regulatory mechanisms, and potential clinical applications in human cancers in order to provide novel perspectives on cancer prognosis and targeted therapy.

Sotatercept for Pulmonary Arterial Hypertension in the Inpatient Setting.

Patients with pulmonary arterial hypertension (PAH) who are admitted to the hospital pose a challenge to the multidisciplinary healthcare team due to the complexity of the pathophysiology of their disease state and PAH-specific medication considerations. Pulmonary arterial hypertension is a progressive disease that may lead to death as a result of right ventricular (RV) failure. During acute on chronic RV failure it is critical to decrease the pulmonary vascular resistance with the goal of improving RV function and prognosis; therefore, aggressive PAH-treatment based on disease risk stratification is essential. Pulmonary arterial hypertension treatment for acute on chronic RV failure can be impacted by end-organ damage, hemodynamic instability, drug interactions, and PAH medications dosage and delivery. Sotatercept, a first in class activin signaling inhibitor that works on the bone morphogenetic protein/activin pathway is on track for Food and Drug Administration approval for the treatment of PAH based on results of recent trials in where the medication led to clinical and hemodynamic improvements, even when added to traditional PAH-specific therapies. The purpose of this review is to highlight important considerations when starting or continuing sotatercept in patients admitted to the hospital with PAH.