Levels Of Activin Research Articles

Tonic activin signaling shapes cellular and synaptic properties of CA1 neurons mainly in dorsal hippocampus

Dorsal and ventral hippocampus serve different functions in cognition and affective behavior, but the underpinnings of this diversity at the cellular and synaptic level are not well understood. We found that the basal level of activin A, a member of the TGF-β family, which regulates hippocampal circuits in a behaviorally relevant fashion, is much higher in dorsal than in ventral hippocampus. Using transgenic mice with a forebrain-specific disruption of activin receptor signaling, we identified the pronounced dorsal-ventral gradient of activin A as a major factor determining the distinct neurophysiologic signatures of dorsal and ventral hippocampus, ranging from pyramidal cell firing, tuning of frequency-dependent synaptic facilitation, to long-term potentiation (LTP), long-term depression (LTD), and de-potentiation. Thus, the strong activin A tone in dorsal hippocampus appears crucial to establish cellular and synaptic phenotypes that are tailored specifically to the respective network operations in dorsal and ventral hippocampus.

Activin levels correlate with lymphocytic infiltration in epithelial ovarian cancer tumors (2304)

Activin levels correlate with lymphocytic infiltration in epithelial ovarian cancer tumors (2304)

Abstract GS.03: Functional Role Of Placental Senescence In Peripartum Cardiomyopathy

Introduction: Peripartum cardiomyopathy (PPCM) and preeclampsia (PEC) are leading causes of maternal mortality with limited therapies. Circulating factors in late pregnancy contribute to cardiac dysfunction in PPCM and PEC. We recently identified senescence-associated secretory proteins (SASP), markers of biological aging, as the most highly upregulated circulating proteins in PPCM and PEC. The mechanisms driving this paradoxical aging pathophysiology in these pregnancy-induced heart failure (HF) syndromes are unknown. Hypothesis: The placenta becomes markedly senescent by term. We hypothesized that 1) amplified placental senescence causes the increase in circulating SASP in PPCM and PEC, and 2) attenuating placental senescence might improve cardiac function in PPCM. Methods: We performed comprehensive senescence assessments in placental samples from women with preeclampsia vs . matched pregnant controls. We assessed the effects of placental senescence in human iPSC-derived cardiomyocytes (iPSC-CM) and the PGC1α-KO PPCM murine model. Results: Placentas from PEC women displayed multiple markers of amplified senescence, including increased p16 and p21 expression (2 & 4 fold, p<0.03), decreased DNA methylation (-1.7 fold, p<0.04), and increased overall SASP expression (2 fold; p<0.001). In iPSC-CM, PEC plasma induced pathologic gene expression profiles (Nppa, Nppb, Myh7) and increased Activin-A signaling (Fstl3, Serpine1, Ccn2), a key SASP factor that contributes to cardiac dysfunction in PEC and PPCM. The senolytic Fisetin attenuated placental senescence in pregnant PGC1α-KO mice, reducing placental p16 and p21 expression (-2 & -3 fold, p<0.01) and Activin-A levels (-2 fold, p<0.03). Compared to vehicle-treated pregnant PGC1α-KO mice, Fisetin-treated animals had 35% higher left ventricular fractional shortening (31% vs . 42%; p<0.001), along with reductions in cardiac Nppa expression and Activin signaling. No changes in cardiac senescence or adverse effects on fetal development were observed with Fisetin. Conclusion: We identify amplified placental senescence as part of the core pathobiology underlying PPCM and PEC, and present proof-of-concept evidence for senolytic therapeutic approaches in pregnancy-induced HF.

P-282 The role of activin A in the development of embryo: a preliminary insight using a mouse in vitro model

Abstract Study question Is activin A involved in the preimplantation development of mouse embryo? Do maternal-derived and zygotic protein have a different impact on embryogenesis? Summary answer Deletion of zygotic activin A does not impair the preimplantation development of mouse embryos. However, reduced level of maternal activin A affects female fertility. What is known already Activin A is a protein secreted by the reproductive system of females, both in mouse and human. Disruption of its signalling pathway is correlated with the occurrence of ectopic pregnancies and miscarriages. Activin A is also a known regulator of the hormone FSH, affecting the growth of ovarian follicles and, consequently, the formation of functional gametes. Furthermore, expression of this protein is detected in embryos themselves and is imperative during postimplantation development. Although activin has been reported to be present from the preimplantation stages, due to the multiple sources of secretion, its role during this period of embryogenesis remains elusive. Study design, size, duration In the first part of our project, we compared the phenotype of zygotic knockout mouse embryos (Inhba−/−, n = 43) with stage-matched heterozygotes (Inhba+/−, n = 113) and wild-type (Inhba+/+, n = 42) embryos. In addition, the blastocyst outgrowth assay has been used as an in vitro implantation model. The second part of our studies focuses on the protein provided by the mother. Using hypomorphic mutants, we investigated the impact of reduced level of activin A on mouse female fertility. Participants/materials, setting, methods We analysed the morphokinetic parameters of Inhba−/−, Inhba+/− and Inhba+/+ embryos by recording their development using time-lapse microscopy. Then blastocysts were immunostained and the percentage of each cell lineage was quantified using Imaris software. To assess the fertility of hypomorphic mice, we mated them with wild-type individuals. We evaluated the time needed to receive the offspring and the size of the litter. Furthermore, we examined the functionality of oocytes of hypomorphs by in vitro fertilisation. Main results and the role of chance We revealed that the deletion of zygotic activin A does not affect the rate and course of development of embryos from the zygote to the blastocyst stage. Inhba−/− embryos have similar timing of cleavage divisions, compaction, cavitation and synchrony of the cleavage rounds to the stage-matched Inhba+/− and Inhba+/+ embryos. Moreover, Inhba−/− embryos do not significantly differ in the number and percentage of cells contributing to the cell lineages of a blastocyst. Despite the reports on the possible involvement of activin A in the embryo implantation process, the obtained Inhba−/− outgrowths have normal morphology and a similar surface area to the corresponding control embryos. Therefore, our results indicate that zygotic activin A is indispensable for preimplantation development and embryo implantation. To study the effect of activin A secreted by the maternal reproductive system on embryogenesis, we used mice with a hypomorphic mutation of the activin A gene. We revealed that homozygotic mice have a characteristic phenotype and significantly reduced fertility. Crossing hypomorphic homozygous females with wild-type males resulted in the pregnancy of only one of the seven females. These results, combined with successful oocyte in vitro fertilisation experiments, point to the role of maternal-derived activin A in mouse reproduction. Limitations, reasons for caution Literature data indicate that oocytes have a pool of protein that is a product of the maternal genome. This maternal activin A can partially compensate for the lack of zygotic protein. Therefore, our further research will address the consequences of maternal and maternal-zygotic activin A knockout on embryo development. Wider implications of the findings Separate examination of zygotic and maternal-derived activin A allowed a comprehensive investigation of the contribution of this protein to mouse reproduction and preimplantation embryo development. Despite using a mouse as a model organism, the obtained results may become an argument for discussion of the impact of activin on human pregnancy. Trial registration number not applicable

Maternal Serum Activin A, Inhibin A and Follistatin-Related Proteins across Preeclampsia: Insights into Their Role in Pathogenesis and Prediction.

Within the endocrine-paracrine signalling network at the maternal-foetal interface, the activin-inhibin-follistatin system modulates extravillous trophoblast invasion, suggesting a potential role in preeclampsia pathogenesis. This study aimed to compile the evidence published in the last decade regarding the variation in maternal serum activins, inhibin- and follistatin-related proteins in preeclamptic pregnancies compared to healthy pregnancies, and to discuss their role in predicting and understanding the pathophysiology of preeclampsia. A scoping review was conducted in MEDLINE, EMBASE and LILACS databases to identify studies published within the last ten years (2012-2022). Thirty studies were included. None of the studies addressed maternal serum changes of isoforms different from activin A, inhibin A, follistatin, and follistatin-like 3. Sixteen studies evaluated the potential of these isoforms in predicting preeclampsia through the area under the curve from a receiver operating characteristic curve. In preeclampsia, inhibin A is upregulated in all trimesters, whereas activin A increases exclusively in the late second and third trimesters. Serum follistatin levels are reduced in women with preeclampsia during the late second and third trimesters. However, changes in follistatin-like 3 remain inconclusive. Inhibin A and activin A can potentially serve as biomarkers of early-onset preeclampsia based on the outcomes of the receiver operating characteristic curve analysis. Further investigations are encouraged to explore the feasibility of quantifying maternal serum levels of activin A and inhibin A as a clinical tool in early preeclampsia prediction.

Association of activins, follistatins and inhibins with incident hip fracture in women with postmenopausal osteoporosis: a proof of concept, case-control study.

The activins-follistatins-inhibins (AFI) hormonal system is considered to regulate muscle and bone mass. We aimed to evaluate AFI in postmenopausal women with an incident hip fracture. In this post-hoc analysis of a hospital based case-control study, we evaluated circulating levels of the AFI system in postmenopausal women with a low-energy hip fracture admitted for fixation compared with postmenopausal women with osteoarthritis scheduled for arthroplasty. Circulating levels of follistatin (p = 0.008), FSTL3 (p = 0.013), activin B and AB (both p < 0.001), as well as activin AB/follistatin and activin AB/FSTL3 ratios (p = 0.008 and p = 0.029, respectively) were higher in patients than controls in unadjusted models. Differences for activins B and AB remained after adjustment for age and BMI (p = 0.006 and p = 0.009, respectively) and for FRAX-based risk for hip fracture (p = 0.008 and p = 0.012, respectively) but were lost when 25OHD was added to the regression models. Our data indicate no major changes in the AFI system in postmenopausal women at the time of hip fracture compared to postmenopausal women with osteoarthritis except for higher activin B and AB levels, whose significance, however, was lost when 25OHD was added to the adjustment models. Clinical Trials identifier: NCT04206618.

The serum levels of activin A and bone morphogenetic protein-4 and -6 in patients with fibrodysplasia ossificans progressiva

BackgroundFibrodysplasia ossificans progressiva (FOP) is an ultrarare and disabling genetic disorder of connective tissue characterized by congenital malformation of the great toes, and progressive heterotopic ossification (HO) in soft connective tissues. A gain-of-function mutation of activin A receptor type I (ACVR1) enables ACVR1 to recognize activin A as an agonist with bone morphogenetic protein (BMP) signalling that leads to HO. Previous studies confirmed that activin A stimulates BMP signalling in vitro and drives HO in mouse models of FOP. However, the roles for BMP4 and BMP6 in FOP are supported only by correlative evidence in vitro. Thus, it remains unclear whether the circulating levels of activin A, BMP4 and BMP6 correlate with flare-ups in FOP patients. Hence, we investigated the protein levels of activin A, BMP4 and BMP6 in the serum of FOP patients.ResultsWe recruited 16 untreated FOP patients and 16 age- and sex- matched healthy control subjects in this study. The 16 FOP patients were retrospectively divided into the flare-up group (n = 8) and remission group (n = 8) depending on whether they had flare-ups or worsening of any joint movement in the last 6 months. The serum activin A, BMP4 and BMP6 levels were detected by enzyme-linked immunosorbent assay. The serum activin A, BMP4 and BMP6 levels were slightly higher in FOP patients (median: 434.05 pg/mL, 459.48 pg/mL and 67.84 pg/mL) versus healthy control subjects (median: 364.14 pg/mL, 450.39 pg/mL and 55.36 pg/mL). However, there were no statistically significant differences between the two groups (p > 0.05 for all items), nor were there significant differences between the flare-up and remission groups of FOP (p > 0.05 for all items). Univariate and multivariate logistic regression analyses showed that age, sex, and serum activin A, BMP4 and BMP6 levels were not related to flare-up in FOP patients.ConclusionsThere were no significant differences in the serum levels of activin A, BMP4 and BMP6 in FOP patients compared with healthy control subjects. Serum activin A, BMP4 and BMP6 proteins might not be the stimulators for FOP flare-up, and may not be biomarkers for FOP diagnosis.

Serum and Pulmonary Expression Profiles of the Activin Signaling System in Pulmonary Arterial Hypertension.

Activins are novel therapeutic targets in pulmonary arterial hypertension (PAH). We therefore studied whether key members of the activin pathway could be used as PAH biomarkers. Serum levels of activin A, activin B, α-subunit of inhibin A and B proteins, and the antagonists follistatin and follistatin-like 3 (FSTL3) were measured in controls and in patients with newly diagnosed idiopathic, heritable, or anorexigen-associated PAH (n=80) at baseline and 3 to 4 months after treatment initiation. The primary outcome was death or lung transplantation. Expression patterns of the inhibin subunits, follistatin, FSTL3, Bambi, Cripto, and the activin receptors type I (ALK), type II (ACTRII), and betaglycan were analyzed in PAH and control lung tissues. Death or lung transplantation occurred in 26 of 80 patients (32.5%) over a median follow-up of 69 (interquartile range, 50-81) months. Both baseline (hazard ratio, 1.001 [95% CI, 1.000-1.001]; P=0.037 and 1.263 [95% CI, 1.049-1.520]; P=0.014, respectively) and follow-up (hazard ratio, 1.003 [95% CI, 1.001-1.005]; P=0.001 and 1.365 [95% CI, 1.185-1.573]; P<0.001, respectively) serum levels of activin A and FSTL3 were associated with transplant-free survival in a model adjusted for age and sex. Thresholds determined by receiver operating characteristic analyses were 393 pg/mL for activin A and 16.6 ng/mL for FSTL3. When adjusted with New York Heart Association functional class, 6-minute walk distance, and N-terminal pro-B-type natriuretic peptide, the hazard ratios for transplant-free survival for baseline activin A <393 pg/mL and FSTL3 <16.6 ng/mL were, respectively, 0.14 (95% CI, 0.03-0.61; P=0.009) and 0.17 (95% CI, 0.06-0.45; P<0.001), and for follow-up measures, 0.23 (95% CI, 0.07-0.78; P=0.019) and 0.27 (95% CI, 0.09-0.78, P=0.015), respectively. Prognostic values of activin A and FSTL3 were confirmed in an independent external validation cohort. Histological analyses showed a nuclear accumulation of the phosphorylated form of Smad2/3, higher immunoreactivities for ACTRIIB, ALK2, ALK4, ALK5, ALK7, Cripto, and FSTL3 in vascular endothelial and smooth muscle layers, and lower immunostaining for inhibin-α and follistatin. These findings offer new insights into the activin signaling system in PAH and show that activin A and FSTL3 are prognostic biomarkers for PAH.

Targeting activins and inhibins to treat reproductive disorders and cancer cachexia.

Although originally characterised as proteins involved in the control of reproductive function, activins, and to a lesser degree inhibins, are also important regulators of homeostasis in extragonadal tissues. Accordingly, disrupted inhibin/activin expression can have detrimental effects not only for fertility and fecundity, but also for the regulation of muscle, fat and bone mass. Indeed, only recently, two complementary mouse models of inhibin designed to lack bioactivity/responsiveness, revealed that inhibin A/B deficiency during pregnancy, restricts embryo and foetal survival. Conversely, hyper elevated levels of activin A/B, as are frequently observed in patients with advanced cancers, can not only promote gonadal tumour growth but also cancer-cachexia. As such, it is not surprising that inhibin/activin genetic variations or altered circulating levels have been linked to reproductive disorders and cancer. Whilst some of the detrimental health effects associated with disrupted inhibin/activin levels can be attributed to accompanied changes in circulating follicle stimulating hormone (FSH) levels, there is now abundant evidence that activins, in particular, have fundamental FSH-independent tissue homeostatic roles. Increased understanding of inhibin/activin activity, garnered over several decades, has enabled the development of targeted therapies with applications for both reproductive and extra-gonadal tissues. Inhibin- or activin-targeted technologies have been shown not just to enhance fertility and fecundity, but also to reduce disease severity in models of cancer cachexia. Excitingly, these technologies are likely to benefit human medicine and be highly valuable to animal breeding and veterinary programs.

Capsaicin attenuates excitotoxic-induced neonatal brain injury and brain mast cell-mediated neuroinflammation in newborn rats

Excitotoxicity and neuroinflammation are key contributors to perinatal brain injuries. Capsaicin, an active ingredient of chili peppers, is a potent exogenous agonist for transient receptor potential vanilloid 1 receptors. Although the neuroprotective and anti-inflammatory effects of capsaicin are well-documented, its effects on excitotoxic-induced neonatal brain injury and neuroinflammation have not previously been investigated. The aim of this study was to investigate the effects of capsaicin on brain damage, brain mast cells, and inflammatory mediators in a model of ibotenate-induced excitotoxic brain injury in neonatal rats.P5 rat-pups were intraperitoneally injected with vehicle, 0.2-, 1-, and 5-mg/kg doses of capsaicin, or the NMDA (N-methyl-d-aspartate) receptor antagonist MK-801 (dizocilpine), 30 min before intracerebral injection of 10 μg ibotenate. The naive-control group received no substance administration. The rat pups were sacrificed one or five days after ibotenate injection. Levels of activin A and interleukin (IL)-1β, IL-6, and IL-10 in brain tissue were measured using the enzyme-linked immunosorbent assay method. Cortex and white matter thicknesses, white matter lesion size, and mast cells were evaluated in brain sections stained with cresyl-violet or toluidine-blue.Capsaicin improved ibotenate-induced white matter lesions and cerebral white and gray matter thicknesses in a dose-dependent manner. In addition, it suppressed the degranulation and increased number of brain mast cells induced by ibotenate. Capsaicin also reduced the excitotoxic-induced production of neuronal survival factor activin A and of the pro-inflammatory cytokines IL-1β, and IL-6 in brain tissue. However, IL-10 levels were not altered by the treatments. MK-801, as a positive control, reversed all these ibotenate-induced changes, further confirming the success of the model.Our findings provide, for the first time, evidence for the therapeutic effects of capsaicin against excitotoxic-induced neonatal brain injury and brain mast cell-mediated neuroinflammation. Capsaicin may therefore be a promising candidate in the prevention and/or reduction of neonatal brain damage.

Serum Levels of Activin A: Predictor of Insulin Resistance and Atherosclerosis in Prediabetics.

Pathological effects of dysglycemia and insulin resistance on atherosclerosis and cardiac remodeling starts as early as in the prediabetic state before the onset of overt diabetes. Activin A is a molecule with multiple functions, including an important part in glucose homeostatic mechanisms as well as inflammatory processes and is therefore being researched as a useful novel biomarker for prompt recognition of the risk of cardiovascular disease (CVD) in prediabetic individuals, thereby helping in disease prognostication and early institution of therapeutic measuresObjective: The study aimed to measure serum levels of activin A in prediabetic patients and evaluate them in comparison to normoglycemic controls. The association of activin A with carotid intima media thickness (CIMT), left ventricular diastolic dysfunction (LVDD), and homeostatic assessment of insulin resistance (HOMA-IR) was also studiedMaterials and methods: A total of 60 prediabetic cases and 60 normoglycemic control subjects [matched as per age, gender, and body mass index (BMI)] were recruited. Measurement of serum glucose levels (fasting and postprandial) and fasting insulin levels and glycated hemoglobin (HbA1c) levels were done in all the subjects. The values of HOMA-IR were computed using established formulae. Enzyme-linked immunosorbent assay (ELISA) kits were used for the evaluation of serum levels of activin A in both groups. Parameters for the two groups were compared. In the cases, CIMT (using B-mode ultrasound) and LVDD (using two-dimensional (2D) echocardiography) were measured and correlated with activin A levelsResults: Serum fasting insulin (mIU/L) was considerably higher in cases than in the controls (p &lt; 0.001). HOMA-IR median [interquartile range (IQR)] was 4 (3.25-4.93) in some cases, and that in the control group was 1.2 (0.88-1.5) (p &lt; 0.001). Serum activin A levels in the cases group had a median (IQR) of 263.55 (227.1-279.5) ng/mL, which was substantially greater as compared to the control group 159.9 (150.7-178.7) ng/mL (p &lt; 0.001). A significant positive association of serum activin A levels with HOMA-IR (ρ = 0.75, p &lt; 0.001) and CIMT (ρ = 0.50, p &lt; 0.001) was found. In LVDD grade I and II groups, the serum levels of activin A were 257.86 (219.3-271.2) ng/mL and 269 (244.19-291.5) ng/mL, respectively (p = 0.12)Conclusion: A substantial proportion of morbidity and mortality related to dysglycemic states can be attributed to cardiovascular complications. Elevated levels of activin A in prediabetes can act as an indicator of subclinical CVD leading to early diagnosis and intervention.

TGF-Beta Induces Activin A Production in Dermal Fibroblasts Derived from Patients with Fibrodysplasia Ossificans Progressiva.

Fibrodysplasia ossificans progressiva (FOP) is a catastrophic, ultra-rare disease of heterotopic ossification caused by genetic defects in the ACVR1 gene. The mutant ACVR1 receptor, when triggered by an inflammatory process, leads to heterotopic ossification of the muscles and ligaments. Activin A has been discovered as the main osteogenic ligand of the FOP ACVR1 receptor. However, the source of Activin A itself and the trigger of its production in FOP individuals have remained elusive. We used primary dermal fibroblasts from five FOP patients to investigate Activin A production and how this is influenced by inflammatory cytokines in FOP. FOP fibroblasts showed elevated Activin A production compared to healthy controls, both in standard culture and osteogenic transdifferentiation conditions. We discovered TGFβ1 to be an FOP-specific stimulant of Activin A, shown by the upregulation of the INHBA gene and protein expression. Activin A and TGFβ1 were both induced by BMP4 in FOP and control fibroblasts. Treatment with TNFα and IL6 produced negligible levels of Activin A and TGFβ1 in both cell groups. We present for the first time TGFβ1 as a triggering factor of Activin A production in FOP. As TGFβ1 can promote the induction of the main driver of FOP, TGFβ1 could also be considered a possible therapeutic target in FOP treatment.

Prognostic significance of activin A in adult Egyptian patients with acute lymphoblastic leukemia

Abstract Background Activin A belongs to the transforming growth factor-beta superfamily of cytokines that exert a plethora of biological functions, including developmental differentiation, sex determination, control of cellular proliferation, migration, and immune responses. Activins are dimeric glycoproteins that play a significant role in reproduction and in endocrine-active tumors, although inhibins and activins have primarily been described in human gonads and identified as modulators of follicle-stimulating hormone production of the pituitary gland, they have also been detected in several solid tumor types, including endocrine-responsive endometrial, ovarian, and breast carcinomas. Their differential expression has suggested their important role in malignant cell transformation, as well as possible roles in cancer differentiation, proliferation, and growth tumors. Aim The aim was to assess expression of activin A in the serum of adult patients with acute lymphoblastic leukemia (ALL) and its influence on remission and survival of ALL patients. Patients and methods Serum activin A was measured using enzyme-linked immunosorbent assay in 30 ALL patients recruited from Hematology and Bone Marrow Transplantation Unit, Ain Shams University Hospitals, and followed for 1 year in comparison with 15 healthy controls. Results Serum level of activin A was elevated in ALL patients in comparison with the control group with a statistically significant difference (P&lt;0.001). A statistically significant negative correlation was detected between age of the patients and activing-A level (P=0.035). The comparison between different outcomes of the patients (remitted, relapsed, and died patients) above and below the mean level of activin A (265.667 ng/ml), was statistically significant (P&lt;0.001). A statistically significant negative correlation was detected between activing-A level in ALL patients and overall survival (P&lt;0.001), and by using the log-rank test, a statistically significant difference (P&lt;0.001) was detected in ALL patients above and below the mean level of activin A. However, a statistically nonsignificant difference was detected between the mean activing-A level in Philadelphia chromosome-positive patients and Philadelphia chromosome-negative patients (P=0.839). Conclusion Activin A can be a useful poor prognostic biomarker in ALL patients, also, it can be used as a predictor for aggressiveness of the disease, resistance, and survival.

Serum activin-A as a predictive marker for postacne scarring

Background Postacne scar is the most distressing sequelae of inflammatory acne vulgaris. It develops owing to abnormal wound healing process in response to inflammation. Activins are members of the family named transforming growth factors-b that are involved in inflammation, immunity, and wound healing.Objective To evaluate human activin-A as a predictive marker for postacne scarring and the effect of treatment with oral isotretinoin on its serum level.Patients and methods A total of 40 patients who presented with either moderate or severe acne vulgaris were selected for this case–control study. Patients were classified into two groups: group A had no scarring and group B had postacne scarring. Group B patients were treated with oral isotretinoin therapy. Measurement of serum activin-A levels was done using the enzyme-linked immunosorbent assay technique.Results The mean serum level of human activin-A was significantly higher in patients with postacne scarring (189.47±59.63 ng/ml) than patients without scarring (155.4±41.19 ng/ml). Moreover, the mean serum level of human activin-A in group B was significantly decreased after treatment with oral isotretinoin. Patients with serum human activin-A level of more than 144.8 ng/ml are more liable to develop postacne scarring with 80.0% sensitivity and 55% specificity.Conclusion Serum level of activin-A could be a good and reliable marker for the prediction of those patients liable to develop postacne scarring, but more in-depth studies are still required to detect the exact pathogenic action of activin-A in the development of acne scars and to test the targeting of activin-A in an attempt to prevent postacne scarring.

Abstract B013: Activin’s influence on the tumor microenvironment in colon cancer

Abstract Background and aims: Activin A (activin) is a key molecule that regulates cell specific and context dependent signaling in tumor growth and metastasis as well as local and systemic inflammatory responses. Understanding the link between tumor-promotive and inflammatory effects may provide a novel opportunity for targeted therapy in colorectal cancer (CRC). We have previously shown that activin signaling promotes epithelial to mesenchymal transition, tumor migration, and that serum activin correlates with advanced stage in CRC patients. Recently, activin has been implicated in enhancing CD4+ to CD8+ communications to promote cytotoxic elimination of tumor cells. We now hypothesize that activin exerts cell-specific effects in the tumor microenvironment (TME) to both promote anti-tumoral activity of immune cells and pro-metastatic behavior of tumor cells in a context-dependent manner. Methods: Western blot and transwell migration assays with and without activin were performed in human epithelial colon cancer cells with varying expression levels of ACVR2 and in human colonic fibroblasts. The influence of the canonical Smad4 pathway was elucidated in a Ts4-Cre;Apcflox;Smad4flox mouse model for CRC. We analyzed a TMA of 1055 stage II and III CRC patients from the QUASAR2 cohort to correlate activin and CD4+ expression with outcome. The TMAs were also analyzed via Digital Spatial Profiling (DSP, NanoString) to determine the immune cell heterogeneity and cell signaling patterns within the tumor microenvironment relative to activin. Results: The non-canonical pAkt pathway is activated in ACVR2-restored but not ACVR2-mutated HCT116+chr2 colon cancer cells, which leads to tumor cell migration in a PI3K-dependent manner. In vivo, ablation of downstream canonical SMAD signaling is associated with elevated activin, alpha-SMA and pAkt and increases in tissue dysplasia, intestinal stromal disorganization, and animal mortality. While there are direct pro-metastatic effects of activin on tumor cells, activin expression in the TME of stage II or III CRC patients is associated with elevated CD4 and survival benefit (High activin/high CD4: 1.665 hazard ratio, 95% Cl of ratio 1.379 to 2.010). DSP analysis confirmed co-localization of activin with immune cells in the TME which influences cell signaling patterns found in these regions. Conclusion: In colon cancer cells, activin leads to preferential prometastatic PI3K/Akt pathway activation. Within the TME, high levels of activin in the presence of CD4+ T-cells is associated with better outcomes in CRC patients. This work lays the foundation to further study context-dependent activin signaling as an adjunct or target in CRC. Citation Format: Mark B. Wiley, Jessica Bauer, Kunaal Mehrotra, David N. Church, Rachel S. Kerr, David J. Kerr, Paul Grippo, Barbara Jung. Activin’s influence on the tumor microenvironment in colon cancer [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer; 2022 Oct 1-4; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_1):Abstract nr B013.

Reconstructing gene regulatory networks of biological function using differential equations of multilayer perceptrons

BackgroundBuilding biological networks with a certain function is a challenge in systems biology. For the functionality of small (less than ten nodes) biological networks, most methods are implemented by exhausting all possible network topological spaces. This exhaustive approach is difficult to scale to large-scale biological networks. And regulatory relationships are complex and often nonlinear or non-monotonic, which makes inference using linear models challenging.ResultsIn this paper, we propose a multi-layer perceptron-based differential equation method, which operates by training a fully connected neural network (NN) to simulate the transcription rate of genes in traditional differential equations. We verify whether the regulatory network constructed by the NN method can continue to achieve the expected biological function by verifying the degree of overlap between the regulatory network discovered by NN and the regulatory network constructed by the Hill function. And we validate our approach by adapting to noise signals, regulator knockout, and constructing large-scale gene regulatory networks using link-knockout techniques. We apply a real dataset (the mesoderm inducer Xenopus Brachyury expression) to construct the core topology of the gene regulatory network and find that Xbra is only strongly expressed at moderate levels of activin signaling.ConclusionWe have demonstrated from the results that this method has the ability to identify the underlying network topology and functional mechanisms, and can also be applied to larger and more complex gene network topologies.

RF19 | PSUN383 Potential Role of Activin A During Pancreatic Acinar-to-Ductal Metaplasia of Orthotopic Pancreatic Tumor Mice

Abstract Pancreatic ductal adenocarcinoma (PDAC) comprises more than 90% of pancreatic cancer cases and commonly harbors mutations in KRAS and TP53. PDAC is the third leading cause of cancer-related deaths in the US with approximately 10% 5-year relative survival rate. The poor survival rate largely pertains to aggressive growth following metastasis and limited understanding of prognostic factors. Accumulated evidence indicates that PDAC survival rates are inversely correlated with the pancreatic gene expression of INHBA, which encodes inhibin βA, and circulating levels of activin A (a dimer of inhibin βA), which is overexpressed in pancreatic cancer cells. However, potential mechanisms supporting the correlations have remained unclear. PDAC is etiologically related to sustained metaplasia of acinar cells to ductal-like cells (ADM). Therefore, in this study, we tested the hypothesis that activin A plays a tumor-promoting role via ADM. We implanted mouse PDAC KPC (KrasG12D and Tp53R172H) cells into the pancreata of C57BL/6 male mice and divided them into four groups; sham and three groups of orthotopic mice intraperitoneally (IP) injected with either no (TO), scramble (sc) or inhba siRNA (inhba) packaged with CPX nanoparticles, which previously exhibited tumor-targeted delivery, starting on postoperative day 4. On day 16, blood and tissues were harvested for analyses of tumor-related prognostic blood markers and tumor histology. Implanted KPC cells significantly elevated serum activin A levels and induced tumors as demonstrated by the accumulation of SOX9-positive ADM and a-SMA-positive fibroblasts when compared to sham group. Also, metastases occurred to the liver, spleen, kidney, and intestine. No differences were observed between TO and sc groups. However, when compared to sc group, inhba group had significantly suppressed serum activin A levels and reduced tumor size. Statistically, inhba group had fewer metastases and longer survival rates. Histologically, inhba group exhibited more amylase-positive acini conserved and less accumulation of a-SMA-positive cells in the pancreas. Further, the expression of activin A receptor type 2B (ACVR2B) was greatly induced on the acinar cells undergoing ADM transition in sc group, whereas such expression was subdued in inhba group. Collectively, our data indicate that inhba suppression impedes ADM mediated by KPC cells in mice and suggests activin A as one of tumor-initiating factors. It warrants further investigations in human PDAC models and clinical settings to test the potential therapeutic roles of targeting tumor INHBA in early PDAC development. Presentation: Sunday, June 12, 2022 12:30 p.m. - 12:35 p.m., Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.

The Effects of Hydroalcoholic Extract of Silk Cocoon on Hypothalamic-Pituitary -Gonadal Axis in Streptozotocin-Induced Diabetic Male Rats.

Background Diabetes mellitus impairs the reproductive system by damaging the glands and changing their function and hormone secretions. Given the previous studies on medical properties of silk cocoon, the aim of this study was to investigate the effect of the hydroalcoholic extract of silk cocoon on pituitary-gonadal axis hormones and the testis changes in diabetic male rats. Methods In this experimental study, 35 male rats were divided into 5 equal groups. Control (C), nontreated diabetic rats (DNT1), and experimental diabetic rats treated (DT1) with a silk cocoon extract at concentrations of 200, 400, and 800 mg/kg for 56 days. Diabetes was induced by an injection of streptozotocin. Blood sampling was performed by the tail and heart after fasting. Body weight, serum levels of glucose, prolactin, leptin, inhibin A, IGF-2, activin A, insulin, LH, testosterone, FSH, and GnRH were measured along with the testis weight and diameter as the outcome of the study. Data were analyzed by SPSS version 20. Results Investigation of hormonal factors indicated that all diabetic groups had higher prolactin, inhibin A levels than those in C group and lower leptin, IGF-2, activin A, insulin, LH, testosterone, FSH, and GnRH levels than controls. Silk cocoon treatment significantly decreased prolactin and inhibin in comparison of DNT1 group. While there was a significant increase in leptin, IGF-2, activin A, insulin, LH, testosterone, FSH, and GnRH levels compared with DNT1 (P < 0.05). A significant decrease in both the testis weights and diameters was observed in diabetic male rats compared to controls (P < 0.05). While silk cocoon treatment improved gonadal weight, the diameter of tunica albuginea, and seminiferous tubules as long as increased in numbers of spermatocytes and Sertoli-Leydig cells. Spermatogonia, spermatocyte, spermatid, spermatozoid, Sertoli cells, and Leydig cell count were significantly lower in the DNT1 group in comparison with the control group, while all groups receiving the highest dose of SC800 mg/kg daily had a higher count of cells than the DNT1 group. Conclusion It seems that silk cocoon treatment decreases the effects of diabetes on hypothalamic-pituitary–gonadal axis.

Serum levels of Activin A: Marker of insulin resistance and cardiovascular risk in prediabetics.

A substantial proportion of health burden in diabetic individuals can be attributed to cardiovascular complications. The increasing risk of cardiovascular complications along the spectrum of dysglycemia warrants the need to devise novel markers for early assessment and management. Activin A is a multifunctional cytokine with an important role in glucose homeostasis and vascular diseases. It can thus serve as a guide for early identification of cardiovascular disease (CVD) risk in prediabetes. The aim of the study was to measure serum levels of activin A in prediabetics, compare them with normoglycemic controls and find the correlation of activin A with markers of insulin resistance such as the homeostatic model assessment of insulin resistance (HOMA-IR). Sixty prediabetic patients and similar age-, sex-, blood pressure-, and BMI-matched controls were recruited in the study. In both groups, serum levels of fasting blood glucose and post prandial glucose, glycated hemoglobin (HbA1c) and fasting insulin were measured. HOMA-IR values were calculated. Serum activin A levels were measured in both groups using ELISA. The obtained values were compared between the two groups. The median (IQR) of s. fasting insulin (mIU/L) in the case group was 15.3 (12.2-18.62) which was significantly higher than that in the control group, which was 6 (4.2-7.3). The median (IQR) of s. activin A (ng/mL) in the case group was 263.55 (227.18-279.56) which was significantly higher than that in the control group, which was 159.9 (150.73-178.75) (P < 0.001). There was a very strong positive correlation of s. activin A (ng/mL) with s. fasting insulin (mIU/L) and HOMA-IR (rho = 0.67 and 0.75, respectively, P < 0.001). Activin A, if combined with other atherosclerotic markers, might improve the assessment of insulin resistance and cardiovascular risk in prediabetics and lead to focus on lifestyle modifications and preventive medical therapy, thereby contributing to the prevention of CVD-related mortality and morbidity in these patients.

Clinical value of activin A in early identification of moderate and severe acute pancreatitis: a prospective study

To explore the value of serum activin A (ACT-A) level in early identification of moderate and severe acute pancreatitis (AP). A prospective case control study was conducted. A total of 120 patients with AP admitted to department of hepatobiliary surgery of Affiliated Nanhua Hospital of Hengyang Medical College of University of South China between October 2020 and April 2022 were recruited. According to the revised Atlanta classification, all patients were classified into mild AP group and moderate-to-severe AP group. The blood samples within 24 hours of onset were drawn, and the serum ACT-A and C-reactive protein (CRP) levels were detected by enzyme-linked immunosorbent assay (ELISA). The Ranson score and the modified CT severity index (MCTSI) were performed. Pearson correlation method was used to analyze the correlation of various parameters. The receiver operator characteristic curve (ROC curve) was plotted to analyze the predictive value of ACT-A and CRP for moderate-to-severe AP. A total of 120 patients with AP were enrolled, including 83 patients with mild AP and 37 patients with moderate-to-severe AP. Serum ACT-A and CRP levels within 24 hours of onset in the moderate-to-severe AP group were significantly higher than those in the mild AP group [ACT-A (ng/L): 140.4±37.7 vs. 53.9±30.5, lg CRP: 1.42±0.91 vs. 0.77±0.70, both P < 0.01], and the Ranson score and MCTSI score were also significantly higher than those in the mild AP group (Ranson score: 5.3±1.3 vs. 1.8±1.6, MCTSI score: 5.5±1.0 vs. 2.7±1.2, both P < 0.01). Correlation analysis showed that the serum ACT-A level was positively correlated with serum CRP level, Ranson score and MCTSI score (R2 value was 0.272, 0.841, 0.616, respectively, all P < 0.05). ROC curve analysis showed that the serum ACT-A, CRP and Ranson score had predictive value for moderate-to-severe AP. The area under the ROC curve (AUC) was 0.948 [95% confidence interval (95%CI) was 0.909-0.986], 0.711 (95%CI was 0.606-0.815), 0.946 (95%CI was 0.910-0.982), respectively. When serum ACT-A > 112.6 ng/L, the sensitivity and specificity of predicting moderate-to-severe AP were 78.38% and 96.39%, respectively, which was better than serum CRP with sensitivity and specificity of 72.92% and 66.27%, respectively, and the specificity was better than Ranson score (71.08%). ACT-A can be detected in the early stage of AP, and it is positively correlated with the disease severity, which can early identify moderate-to-severe AP.