RESUMEN
Activin A (Act A) has been reported to promote oligodendrocyte progenitor cell (OPC) differentiation in vitro and improve neurological outcomes in adult mice. However, the roles and mechanisms of action of Act A in preterm brain injury are unknown. In the present study, P5 rats were subjected to hypoxiaischemia to establish a neonatal white matter injury (WMI) model and Act A was injected via the lateral ventricle. Pathological characteristics, OPC differentiation, myelination, and neurological performance were analyzed. Further, the involvement of the Noggin/BMP4/Id2 signaling pathway in the roles of Act A in WMI was explored. Act A attenuated pathological damage, promoted OPC differentiation, enhanced myelin sheath and myelinated axon formation, and improved neurological performance of WMI rats. Moreover, Act A enhanced noggin expression, which, in turn, inhibited the expression of bone morphogenetic protein 4 (BMP4) and inhibitor of DNA binding 2 (Id2). Furthermore, upregulation of Id2 completely abolished the rescue effects of Act A in WMI rats. In conclusion, the present findings suggested that Act A rescues preterm brain injury via targeting a novel Noggin/BMP4/Id2 signaling pathway.
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Activinas , Lesiones Encefálicas , Animales , Ratones , Ratas , Activinas/farmacología , Activinas/uso terapéutico , Proteína Morfogenética Ósea 4/efectos de los fármacos , Proteína Morfogenética Ósea 4/metabolismo , Lesiones Encefálicas/tratamiento farmacológico , Lesiones Encefálicas/metabolismo , Transducción de Señal/fisiología , Proteína 2 Inhibidora de la Diferenciación/efectos de los fármacos , Proteína 2 Inhibidora de la Diferenciación/metabolismoRESUMEN
Several novel myelodysplastic syndromes (MDS) treatment drugs are being developed, and luspatercept and oral hypomethylating medicines have already been licensed in the United States and other countries. Luspatercept is a ligand trap that inhibits SMAD2/3 signals by combining the extracellular domain of the activin type IIA receptor with the human immunoglobulin G1 Fc domain. In the phase 2 study for low-risk MDS, the hematological improvement-erythroid (HI-E) was found in 63% of patients, and in the phase 3 study for transfusion-dependent low-risk MDS with ring sideroblasts, 38% of patients achieved transfusion independence. A combination of oral decitabine with oral cedazuridine, an inhibitor of cytidine deaminase, which metabolizes decitabine, demonstrated pharmacological equivalence with intravenous decitabine and has overall response rates of 60% and 43% for high-risk MDS in phase 2 and 3 trials, respectively. Furthermore, oral azacitidine and its combination with oral cedazuridine have been under development.
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Síndromes Mielodisplásicos , Receptores de Activinas Tipo II , Activinas/uso terapéutico , Azacitidina/uso terapéutico , Citidina Desaminasa , Decitabina/uso terapéutico , Humanos , Fragmentos Fc de Inmunoglobulinas , Ligandos , Síndromes Mielodisplásicos/tratamiento farmacológico , Proteínas Recombinantes de Fusión , Resultado del TratamientoRESUMEN
BACKGROUND: Activin-A, a transforming growth factor ß family member, is secreted by many cancer types and is often associated with poor disease prognosis. Previous studies have shown that Activin-A expression can promote cancer progression and reduce the intratumoral frequency of cytotoxic T cells. However, the underlying mechanisms and the significance of Activin-A expression for cancer therapies are unclear. METHODS: We analyzed the expression of the Activin-A encoding gene INHBA in melanoma patients and the influence of its gain- or loss-of-function on the immune infiltration and growth of BRAF-driven YUMM3.3 and iBIP2 mouse melanoma grafts and in B16 models. Using antibody depletion strategies, we investigated the dependence of Activin-A tumor-promoting effect on different immune cells. Immune-regulatory effects of Activin-A were further characterized in vitro and by an adoptive transfer of T cells. Finally, we assessed INHBA expression in melanoma patients who received immune checkpoint therapy and tested whether it impairs the response in preclinical models. RESULTS: We show that Activin-A secretion by melanoma cells inhibits adaptive antitumor immunity irrespective of BRAF status by inhibiting CD8+ T cell infiltration indirectly and even independently of CD4 T cells, at least in part by attenuating the production of CXCL9/10 by myeloid cells. In addition, we show that Activin-A/INHBA expression correlates with anti-PD1 therapy resistance in melanoma patients and impairs the response to dual anti-cytotoxic T-Lymphocyte associated protein 4/anti-PD1 treatment in preclinical models. CONCLUSIONS: Our findings suggest that strategies interfering with Activin-A induced immune-regulation offer new therapeutic opportunities to overcome CD8 T cell exclusion and immunotherapy resistance.
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Activinas , Melanoma , Activinas/metabolismo , Activinas/uso terapéutico , Animales , Linfocitos T CD8-positivos , Humanos , Inmunidad Celular , Subunidades beta de Inhibinas , Melanoma/tratamiento farmacológico , Melanoma/genética , Melanoma/inmunología , Ratones , Proteínas Proto-Oncogénicas B-raf/metabolismoRESUMEN
BACKGROUND: Despite advances in immunotherapy and targeted therapy, platinum-based chemotherapy remains crucial for many patients with advanced non-small cell lung cancer (NSCLC). Resistance to platinum chemotherapy is common, and predictive biomarkers are needed to tailor treatment to patients likely to respond. In vitro evidence implicates the transforming growth factor-ß (TGF-ß) superfamily ligands activin-A and growth differentiation factor 11 (GDF-11) in innate platinum resistance. We performed a validation study to assess their utility as predictive biomarkers of platinum chemotherapy response in advanced NSCLC. PATIENTS AND METHODS: Our study included 123 adult patients with advanced NSCLC without a driver mutation treated with platinum chemotherapy. 98 patients were from a retrospective cohort and 25 from a prospective cohort. We performed immunohistochemistry staining for Activin-A, GDF-11 and TGF-ß on tumour samples for each patient and analysed IHC expression with objective radiological response and overall survival. RESULTS: The overall median survival was 14.8 months. We performed statistical analysis around a cytoplasmic score of 8/18 for Activin-A and GDF-11 based on previously published work, and 110/30 for TGF-ß based on a calculated cutpoint for significance. No survival difference was detected between these groups for Activin-A (p=0.35), GDF-11 (p=0.57) or TGF-ß (p=0.34). There was no association between rates of progressive disease and high Activin-A expression (p=0.43), high GDF-11 expression (p=1.0) or high TGF-ß expression p=0.89). CONCLUSION: Within the confines of our study, Activin-A, GDF-11 and TGF-ß expression was not a predictor of objective radiological response to chemotherapy or overall survival.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Compuestos Organoplatinos , Activinas/metabolismo , Activinas/uso terapéutico , Adulto , Biomarcadores , Proteínas Morfogenéticas Óseas , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/patología , Factores de Diferenciación de Crecimiento/uso terapéutico , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Compuestos Organoplatinos/uso terapéutico , Platino (Metal)/uso terapéutico , Estudios Prospectivos , Estudios Retrospectivos , Factor de Crecimiento Transformador beta/metabolismo , Factor de Crecimiento Transformador beta/uso terapéutico , Factores de Crecimiento Transformadores/uso terapéuticoRESUMEN
Activin A plays important roles in ischemic injury and white matter remyelination, but its mechanisms are unclear. In this study, the adult male C57BL/6 J mice were used to establish the model of 1 h middle cerebral artery occlusion/reperfusion (MCAO/R) 1 d to 28 d-induced ischemic stroke in vivo. We found that the neurological outcome was positively correlated with the levels of myelin associated proteins (include MAG, CNPase, MOG and MBP, n = 6 per group) both in corpus callosum and internal capsule of mice with ischemic stroke. The dynamic changes of Luxol fast blue (LFB) staining intensity, oligodendrocyte (CC1+) and proliferated oligodendrocyte precursor (Ki67+/PDGFRα+) cell numbers indicated demyelination and spontaneous remyelination occurred in the corpus callosum of mice after 1 h MCAO/R 1 d-28 d (n = 6 per group). Activin receptor type I (ACVR1) inhibitor SB431542 aggregated neurological deficits, and reduced MAG, MOG and MBP protein levels of mice with ischemic stroke (n = 6 per group). Meanwhile, recombinant mouse (rm) Activin A enhanced the neurological function recovery, MAG, MOG and MBP protein levels of mice with 1 h MCAO/R 28 d. In addition, the injection of AAV-based ACVR1B shRNA with Olig2 promoter could reverse rmActivin A-induced the increases of CC1+ cell number, LFB intensity, MAG, MOG and MBP protein levels in the corpus callosum (n = 6 per group), and neurological function recovery (n = 10 per group) of mice with 1 h MCAO/R 28 d. These results suggested that Activin A improves the neurological outcome through promoting oligodendroglial ACVR1B-mediated white matter remyelination of mice with ischemic stroke, which may provide a potential therapeutic strategy for ischemic stroke.
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Receptores de Activinas Tipo I/metabolismo , Activinas/uso terapéutico , Accidente Cerebrovascular Isquémico/tratamiento farmacológico , Vaina de Mielina/efectos de los fármacos , Fármacos Neuroprotectores/uso terapéutico , Oligodendroglía/efectos de los fármacos , Sustancia Blanca/patología , Receptores de Activinas Tipo I/genética , Animales , Recuento de Células , Proliferación Celular/efectos de los fármacos , Cuerpo Calloso/patología , Enfermedades Desmielinizantes/tratamiento farmacológico , Enfermedades Desmielinizantes/patología , Accidente Cerebrovascular Isquémico/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Vaina de Mielina/patología , Daño por Reperfusión/tratamiento farmacológico , Daño por Reperfusión/genética , Daño por Reperfusión/patología , Resultado del TratamientoRESUMEN
Anemia of lower-risk myelodysplastic syndromes (MDSs) and primary myelofibrosis (PMF) generally becomes resistant to available treatments, leading to red blood cell (RBC) transfusions, iron overload, shortened survival, and poor quality of life. The transforming growth factor-ß superfamily, including activins and growth differentiation factors (GDFs), is aberrantly expressed in lower-risk MDSs and PMF. Luspatercept (and sotatercept), ligand traps that particularly inhibit GDF11, lead to RBC transfusion independence in 10% to 50% of lower-risk MDSs resistant to available treatments, and have started to be used in PMF.
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Activinas/uso terapéutico , Anemia/terapia , Fragmentos Fc de Inmunoglobulinas/uso terapéutico , Síndromes Mielodisplásicos/terapia , Proteínas Recombinantes de Fusión/uso terapéutico , Receptores de Activinas Tipo II , Anemia/mortalidad , Proteínas Morfogenéticas Óseas/antagonistas & inhibidores , Supervivencia sin Enfermedad , Transfusión de Eritrocitos , Factores de Diferenciación de Crecimiento/antagonistas & inhibidores , Humanos , Sobrecarga de Hierro/etiología , Sobrecarga de Hierro/mortalidad , Síndromes Mielodisplásicos/mortalidad , Tasa de SupervivenciaRESUMEN
ß-thalassemia is a hereditary disorder with limited approved treatment options; patients experience anemia and its complications, including iron overload. The study aim was to determine whether luspatercept could improve anemia and disease complications in patients with ß-thalassemia. This open-label, nonrandomized, uncontrolled study consisted of a 24-week dose-finding and expansion stage (initial stage) and a 5-year extension stage, currently ongoing. Sixty-four patients were enrolled; 33 were non-transfusion dependent (mean hemoglobin, <10.0 g/dL; <4 red blood cell [RBC] units transfused per 8 weeks), and 31 were transfusion dependent (≥4 RBC units per 8 weeks). Patients received 0.2 to 1.25 mg/kg luspatercept subcutaneously every 21 days for ≥5 cycles (dose-finding stage) and 0.8 to 1.25 mg/kg (expansion cohort and 5-year extension). The primary end point was erythroid response, defined as hemoglobin increase of ≥1.5 g/dL from baseline for ≥14 consecutive days (without RBC transfusions) for non-transfusion-dependent patients or RBC transfusion burden reduction ≥20% over a 12-week period vs the 12 weeks before treatment for transfusion-dependent patients. Eighteen non-transfusion-dependent patients (58%) receiving higher dose levels of luspatercept (0.6-1.25 mg/kg) achieved mean hemoglobin increase ≥1.5 g/dL over ≥14 days vs baseline. Twenty-six (81%) transfusion-dependent patients achieved ≥20% reduction in RBC transfusion burden. The most common grade 1 to 2 adverse events were bone pain, headache, and myalgia. As of the cutoff, 33 patients remain on study. In this study, a high percentage of ß-thalassemia patients receiving luspatercept had hemoglobin or transfusion burden improvements. These findings support a randomized clinical trial to assess efficacy and safety. This study was registered at www.clinicaltrials.gov as #NCT01749540 and #NCT02268409.
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Activinas/uso terapéutico , Transfusión de Eritrocitos/estadística & datos numéricos , Hemoglobinas/análisis , Fragmentos Fc de Inmunoglobulinas/uso terapéutico , Proteínas Recombinantes de Fusión/uso terapéutico , Talasemia beta/tratamiento farmacológico , Receptores de Activinas Tipo II , Adulto , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Adulto JovenRESUMEN
PURPOSE OF REVIEW: Anaemia is a common haematological presentation in patients with bone marrow failure, yet a challenging condition to treat. As anaemia has a direct impact on the patient's symptoms, managing anaemia in the common bone marrow failure conditions, such as myelodysplastic syndrome will help to improve the quality of life. This review discusses the available treatment options and the benefit of improving the haemoglobin level. RECENT FINDINGS: Managing anaemia effectively has shown to improve the patient outcome, yet treatment option remain limited. Recently, activin inhibitors such as Luspatercept have shown to be effective in patients' refractory to ESAs and further clinical trials are ongoing to explore this further. SUMMARY: Transfusion still remains the mainstay of treatment in patients not suitable, lost response or refractory to erythropoiesis-stimulating agents (ESAs). Majority of these patients are not suitable for definite treatment options such as bone marrow transplantation. The aim of treatment remains improving the quality of life and newer therapeutic options may offer better and more sustained response.
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Activinas/uso terapéutico , Anemia Aplásica/complicaciones , Anemia/tratamiento farmacológico , Anemia/etiología , Enfermedades de la Médula Ósea/complicaciones , Hematínicos/uso terapéutico , Hemoglobinuria Paroxística/complicaciones , Fragmentos Fc de Inmunoglobulinas/uso terapéutico , Proteínas Recombinantes de Fusión/uso terapéutico , Receptores de Activinas Tipo II , Anemia/terapia , Transfusión Sanguínea/métodos , Trastornos de Fallo de la Médula Ósea , Humanos , Calidad de VidaRESUMEN
PURPOSE OF REVIEW: Sotatercept and luspatercept are recombinant soluble activin type-II receptor-IgG-Fc fusion proteins that are tested in clinical trials for the treatment of various types of anemias, including renal anemia. The mechanism of the action of the novel drugs is incompletely understood, but it seems to be based on the inactivation of soluble proteins of the transforming growth factor-ß (TGFß) family. This review considers pros and cons of the clinical use of the drugs in reference to the current therapy with recombinant erythropoiesis-stimulating agents (ESAs). RECENT FINDINGS: One or more activin type-II receptor (ActRII) ligands appear to inhibit erythroid precursors, for example growth and differentiation factor 11. Trapping of these ligands by the recombinant ActRII fusion proteins, sotatercept and luspatercept increases red blood cell numbers and hemoglobin levels in humans. Reportedly, the novel compounds were well tolerated in trials on healthy volunteers and patients suffering from anemia due to chronic kidney disease or malignancies. On approval, the drugs may prove particularly useful in patients suffering from ineffective erythropoiesis, such as in myelodysplastic syndrome, multiple myeloma or ß-thalassemia, where ESAs are of little use. Independent of their effect on erythropoiesis, ActRII ligand traps were found to exert beneficial effects on renal tissue in experimental animals. SUMMARY: ESAs are likely to remain standard of care in renal anemia. There is a need for a better understanding of the effects of ActRII ligand traps on TGFß-like proteins. The novel drugs have not been approved for sale as therapeutics so far. Their long-term efficacy and safety still needs to be proven, particularly with respect to immunogenicity. Antifibrotic effects may be worthy to be investigated in humans.
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Activinas/farmacología , Anemia/tratamiento farmacológico , Eritropoyesis/efectos de los fármacos , Hematínicos/uso terapéutico , Fragmentos Fc de Inmunoglobulinas/farmacología , Proteínas Recombinantes de Fusión/farmacología , Insuficiencia Renal Crónica/complicaciones , Receptores de Activinas/efectos de los fármacos , Receptores de Activinas Tipo II , Activinas/metabolismo , Activinas/uso terapéutico , Anemia/etiología , Animales , Eritropoyesis/fisiología , Hematínicos/farmacología , Humanos , Fragmentos Fc de Inmunoglobulinas/uso terapéutico , Ligandos , Proteínas Recombinantes de Fusión/uso terapéutico , Factor de Crecimiento Transformador beta/antagonistas & inhibidoresRESUMEN
INTRODUCTION: Regular transfusion and iron chelation are the current treatment of severe forms of thalassemia. As a consequence of this demanding supportive treatment, there are several unmet therapeutic needs. Due to a deeper understanding in the pathophysiology of thalassemia, new therapeutic strategies have been developed that are now in pre-clinical and clinical trials. Areas covered: Activin receptor ligand traps (luspatercept and sotatercept), drugs targeting ineffective erythropoiesis, showed encouraging results in Phase I and II clinical trials. A phase III clinical trial is currently ongoing. Ruxolitinib, a Jak2 inhibitor, has been tested to limit stress erythropoiesis in a phase II clinical trial. In addition, improvement in iron chelation has been developed. Moreover, several trials of gene therapy are currently active in different countries with different lentiviral vectors. Expert opinion: The most promising molecules are the activin receptor ligand traps. Together with gene therapy these could be an alternative to bone marrow transplant, aiming towards a curative strategy. The main limit to gene therapy seems to be the conditioning regimen, thus an in vivo gene therapy would be more suitable. At pre-clinical level gene editing is showing extremely encouraging results.
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Diseño de Fármacos , Drogas en Investigación/uso terapéutico , Talasemia/tratamiento farmacológico , Receptores de Activinas Tipo II , Activinas/farmacología , Activinas/uso terapéutico , Animales , Ensayos Clínicos Fase I como Asunto , Ensayos Clínicos Fase II como Asunto , Drogas en Investigación/farmacología , Eritropoyesis/efectos de los fármacos , Edición Génica/métodos , Terapia Genética/métodos , Humanos , Fragmentos Fc de Inmunoglobulinas/farmacología , Fragmentos Fc de Inmunoglobulinas/uso terapéutico , Nitrilos , Pirazoles/farmacología , Pirazoles/uso terapéutico , Pirimidinas , Proteínas Recombinantes de Fusión/farmacología , Proteínas Recombinantes de Fusión/uso terapéutico , Talasemia/genética , Talasemia/fisiopatologíaRESUMEN
INTRODUCTION: Erythropoiesis-stimulating agents (ESAs) are not perfect, since they have potential side effects. Iron therapy is also receiving growing attention in recent years. Areas covered: We performed a literature search on PubMed using the following key words: anemia, chronic kidney disease, HIF stabilisers, sotatercept, actin traps, iron, iron-containing phosphate binders, iron dialysate. We reviewed new drugs that are under clinical development to obtain better safety and activity and/or easier and cheaper manufacturing processes in comparison to available ESAs. We also considered new strategies to increase iron stores. Several phase 1 and 2 studies support the beneficial role of increasing Hypoxia Inducible factor (HIF) activity for stimulating endogenous erythropoiesis. Sotatercept and luspatercept, two activin traps, are undergoing clinical development mainly for indications other than CKD. They have the additional effect of improving osteoporosis. Iron-containing phosphate binders have become available recently. Expert opinion: Several medical needs are unmet with ESA. HIF stabilisers are the most appealing drugs undergoing clinical development. They expose patients to lower levels of EPO than ESA, possibly reducing unintended effects. Their long-term safety is still to be demonstrated. One new iron-containing phosphate binders has the potential of combining two indications: hyperphosphoremia and iron deficiency, possibly improving compliance.
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Activinas/uso terapéutico , Anemia/tratamiento farmacológico , Hematínicos/uso terapéutico , Fragmentos Fc de Inmunoglobulinas/uso terapéutico , Proteínas Recombinantes de Fusión/uso terapéutico , Insuficiencia Renal Crónica/tratamiento farmacológico , Receptores de Activinas Tipo II , Activinas/administración & dosificación , Activinas/efectos adversos , Anemia/complicaciones , Eritropoyesis/efectos de los fármacos , Hematínicos/administración & dosificación , Hematínicos/efectos adversos , Humanos , Factor 1 Inducible por Hipoxia/metabolismo , Fragmentos Fc de Inmunoglobulinas/administración & dosificación , Fragmentos Fc de Inmunoglobulinas/efectos adversos , Hierro/metabolismo , Proteínas Recombinantes de Fusión/administración & dosificación , Proteínas Recombinantes de Fusión/efectos adversos , Insuficiencia Renal Crónica/complicaciones , Resultado del TratamientoRESUMEN
Parkinson's disease is a chronic neurodegenerative disease characterized by a significant loss of dopaminergic neurons within the substantia nigra pars compacta region and a subsequent loss of dopamine within the striatum. A promising avenue of research has been the administration of growth factors to promote the survival of remaining midbrain neurons, although the mechanism by which they provide neuroprotection is not understood. Activin A, a member of the transforming growth factor ß superfamily, has been shown to be a potent anti-inflammatory following acute brain injury and has been demonstrated to play a role in the neuroprotection of midbrain neurons against MPP+-induced degeneration in vitro. We hypothesized that activin A may offer similar anti-inflammatory and neuroprotective effects in in vivo mouse models of Parkinson's disease. We found that activin A significantly attenuated the inflammatory response induced by both MPTP and intranigral administration of lipopolysaccharide in C57BL/6 mice. We found that administration of activin A promoted survival of dopaminergic and total neuron populations in the pars compacta region both 8 days and 8 weeks after MPTP-induced degeneration. Surprisingly, no corresponding protection of striatal dopamine levels was found. Furthermore, activin A failed to protect against loss of striatal dopamine transporter expression in the striatum, suggesting the neuroprotective action of activin A may be localized to the substantia nigra. Together, these results provide the first evidence that activin A exerts potent neuroprotection and anti-inflammatory effects in the MPTP and lipopolysaccharide mouse models of Parkinson's disease.
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Activinas/farmacología , Supervivencia Celular/efectos de los fármacos , Neuronas Dopaminérgicas/efectos de los fármacos , Inflamación/tratamiento farmacológico , Intoxicación por MPTP/tratamiento farmacológico , Mesencéfalo/efectos de los fármacos , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina , Activinas/uso terapéutico , Animales , Modelos Animales de Enfermedad , Neuronas Dopaminérgicas/patología , Inflamación/inducido químicamente , Inflamación/patología , Lipopolisacáridos , Intoxicación por MPTP/patología , Masculino , Mesencéfalo/patología , Ratones , Ratones Endogámicos C57BLRESUMEN
Distinct subtypes of lower risk myelodysplastic syndromes display ring sideroblasts in the bone marrow, i. e., erythroid progenitors characterized by excessive iron deposited in the mitochondria. This morphological feature is frequently associated with somatic mutations in components of the splicing machinery that constitutes the underlying molecular principle of the disease. Conventional treatment regimen with erythropoiesis-stimulating agents often fails to induce sustained erythroid improvement in these patients that harbor defects in late-stage erythroblasts downstream of erythropoietin action. In the present review, we will discuss activin receptor ligand traps as novel therapeutic strategies particularly for sideroblastic subgroups of myelodysplastic syndromes that were recently shown to alleviate anemia by specifically inhibiting aberrant TGF-ß signaling and thereby promoting erythroid differentiation.
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Receptores de Activinas Tipo II/metabolismo , Síndromes Mielodisplásicos/patología , Receptores de Activinas Tipo II/antagonistas & inhibidores , Activinas/uso terapéutico , Humanos , Fragmentos Fc de Inmunoglobulinas/uso terapéutico , Sobrecarga de Hierro/complicaciones , Sobrecarga de Hierro/genética , Sobrecarga de Hierro/patología , Síndromes Mielodisplásicos/tratamiento farmacológico , Síndromes Mielodisplásicos/genética , Fosfoproteínas/genética , Factores de Empalme de ARN/genética , Proteínas Recombinantes de Fusión/uso terapéutico , Factor de Crecimiento Transformador beta/antagonistas & inhibidores , Factor de Crecimiento Transformador beta/metabolismoRESUMEN
Parkinson's disease (PD) is one of the most common neurodegenerative diseases. Activins are members of the superfamily of transforming growth factors and have many potential neuroprotective effects. Herein, at the first place, we verified activin B's neuroprotective role in a PD model, and revealed that activin B's fast release has limited function in the PD therapy. To this end, we developed a multi-functional crosslinker based thermosensitive injectable hydrogels to deliver activin B, and stereotactically injected the activin B-loaded hydrogel into the striatum of a mouse model of PD. The histological evaluation showed that activin B can be detected even 5 weeks post-surgery in PD mice implanted with activin B-loaded hydrogels, and activin B-loaded hydrogels can significantly increase the density of tyrosine hydroxylase positive (TH(+)) nerve fibers and reduce inflammatory responses. The behavioral evaluation demonstrated that activin B-loaded hydrogels significantly improved the performance of the mice in the PD model. Meanwhile, we found that hydrogels can slightly induce the activation of microglia cells and astrocytes, while cannot induce apoptosis in the striatum. Overall, our data demonstrated that the developed activin B-loaded hydrogels provide sustained release of activin B for over 5 weeks and contribute to substantial cellular protection and behavioral improvement, suggesting their potential as a therapeutic strategy for PD.
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Activinas/administración & dosificación , Hidrogel de Polietilenoglicol-Dimetacrilato/química , Fármacos Neuroprotectores/administración & dosificación , Enfermedad de Parkinson/tratamiento farmacológico , Activinas/uso terapéutico , Animales , Línea Celular Tumoral , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/patología , Sistemas de Liberación de Medicamentos , Hidrogel de Polietilenoglicol-Dimetacrilato/administración & dosificación , Inyecciones , Masculino , Ratones Endogámicos C57BL , Fármacos Neuroprotectores/uso terapéutico , Enfermedad de Parkinson/patología , ReologíaRESUMEN
Recombinant human erythropoietin (rhEpo, epoetin) has proved beneficial in preventing transfusion-dependent anaemia in patients with chronic kidney disease. Apart from copied epoetins distributed in less regulated markets, 'biosimilar' epoetins have gained currency in many regions, where they compete with the originals and with rhEpo analogues with prolonged survival in circulation ('biobetter'). Recombinant erythropoiesis stimulating agents are potent and well tolerated. However, their production is costly, and they must be administered by the parenteral route. Hence, other anti-anaemia treatments are being evaluated. Clinical trials are being performed with stabilizers of the hypoxia-inducible transcription factors (HIFs), which increase endogenous Epo production. HIF stabilizers are chemical drugs and they are active on oral administration. However, there is fear that they may promote tumour growth. Epo mimetic peptides have also raised expectations. Yet the prototype peginesatide was recalled after just 1 year of its widespread use in the USA because of serious side-effects including cases of death. Most recently, clinical trials have been initiated with sotatercept, a recombinant soluble activin receptor type 2A IgG-Fc fusion protein. Sotatercept binds distinct members of the transforming growth factor-ß family, thereby preventing the inhibitory action of these factors in erythropoiesis. Taken together, rhEpo and its long-acting recombinant analogues will likely remain mainstay of anti-anaemia therapies in the near future.
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Activinas/uso terapéutico , Anemia/tratamiento farmacológico , Biosimilares Farmacéuticos/uso terapéutico , Eritropoyetina/uso terapéutico , Hematínicos/uso terapéutico , HumanosRESUMEN
BACKGROUND: One in eight women will be affected by breast cancer in her lifetime. Approximately 75% of breast cancers express estrogen receptor alpha (ERα) and/or progesterone receptor and these receptors are markers for tumor dependence on estrogen. Anti-estrogenic drugs such as tamoxifen are commonly used to block estrogen-mediated signaling in breast cancer. However, many patients either do not respond to these therapies (de novo resistance) or develop resistance to them following prolonged treatment (acquired resistance). Therefore, it is imperative to continue efforts aimed at developing new efficient and safe methods of targeting ER activity in breast cancer. METHODS: AB215 is a chimeric ligand assembled from sections of Activin A and BMP2. BMP2's and AB215's inhibition of breast cancer cells growth was investigated. In vitro luciferase and MTT proliferation assays together with western blot, RT_PCR, and mRNA knockdown methods were used to determine the mechanism of inhibition of estrogen positive breast cancer cells growth by BMP2 and AB215. Additionally in vivo xenograft tumor model was used to investigate anticancer properties of AB215. RESULTS: Here we report that AB215, a chimeric ligand assembled from sections of Activin A and BMP2 with BMP2-like signaling, possesses stronger anti-proliferative effects on ERα positive breast cancer cells than BMP2. We further show that AB215 inhibits estrogen signaling by inducing expression of inhibitor of DNA binding proteins (IDs). Specifically, we demonstrate that knockdown of ID proteins attenuates the anti-estrogen effects of AB215. Remarkably, we find that AB215 is more effective than tamoxifen in suppressing tumor growth in a xenograft model. CONCLUSION: This study shows that IDs have profound role to inhibit estrogen signaling in ERα positive breast cancer cells, and that engineered TGF-beta ligands may have high therapeutic value.
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Activinas/farmacología , Proteína Morfogenética Ósea 2/farmacología , Neoplasias de la Mama/patología , Proteínas Inhibidoras de la Diferenciación/metabolismo , Proteínas Recombinantes de Fusión/farmacocinética , Transducción de Señal/efectos de los fármacos , Activinas/uso terapéutico , Proteína Morfogenética Ósea 2/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Línea Celular Tumoral , Receptor alfa de Estrógeno/metabolismo , Femenino , Humanos , Proteínas Inhibidoras de la Diferenciación/genética , Células MCF-7 , Trasplante de Neoplasias , Proteínas Recombinantes de Fusión/uso terapéutico , Tamoxifeno/uso terapéutico , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Bone morphogenetic proteins (BMPs) and activins are phylogenetically conserved proteins, belonging to the transforming growth factor-ß superfamily, that signal through the phosphorylation of receptor-regulated Smad proteins, activating different cell responses. They are involved in various steps of skin morphogenesis and wound repair, as can be evidenced by the fact that their expression is increased in skin injuries. BMPs play not only a role in bone regeneration but are also involved in cartilage, tendon-like tissue and epithelial regeneration, maintain vascular integrity, capillary sprouting, proliferation/migration of endothelial cells and angiogenesis, promote neuron and dendrite formation, alter neuropeptide levels and are involved in immune response modulation, at least in animal models. On the other hand, activins are involved in wound repair through the regulation of skin and immune cell migration and differentiation, re-epithelialization and granulation tissue formation, and also promote the expression of collagens by fibroblasts and modulate scar formation. This review aims at enunciating the effects of BMPs and activins in the skin, namely in skin development, as well as in crucial phases of skin wound healing, such as inflammation, angiogenesis and repair, and will focus on the effects of these proteins on skin cells and their signaling pathways, exploring the potential therapeutic approach of the application of BMP-2, BMP-6 and activin A in chronic wounds, particularly diabetic foot ulcerations.
Asunto(s)
Activinas/metabolismo , Proteínas Morfogenéticas Óseas/metabolismo , Pie Diabético/fisiopatología , Piel/metabolismo , Cicatrización de Heridas , Activinas/uso terapéutico , Animales , Proteínas Morfogenéticas Óseas/uso terapéutico , Diferenciación Celular , Humanos , Regeneración , Transducción de Señal , Piel/patologíaRESUMEN
Perifolliculitis capitis abscedens et suffodiens (PCAS) is rare chronic, suppurative and inflammatory scalp disease. Its aetiology and pathogenesis is not completely understood. The treatment is usually difficult and often disappointing. We report a case of 25-year-old male who presented with tender, fluctuant nodules and abscesses, with draining pus and patchy alopecia on his scalp for 3 years. A skin biopsy from scalp lesions revealed features that are characteristic of perifolliculitis. Initially, the patient was treated with periodic incision and drainage of the scalp abscesses. The answer was very poor. When admitted to our department, isotretinoin was started at daily dose of 30 mg, because initially his cholesterol and triglyceride levels were mildly increased. When dose was reduced to 10 mg the levels of cholesterol and triglyceride remained normal. A response to treatment was excellent and rapid. The treatment of PCAS represents usually difficulties and frustration for both the patient and the physician. A long course of isotretinoin can be considered as one of the most effective treatment for PCAS.
Asunto(s)
Foliculitis , Dermatosis del Cuero Cabelludo , Activinas/uso terapéutico , Adulto , Antibacterianos/uso terapéutico , Foliculitis/diagnóstico , Foliculitis/tratamiento farmacológico , Foliculitis/patología , Humanos , Masculino , Metronidazol/uso terapéutico , Dermatosis del Cuero Cabelludo/diagnóstico , Dermatosis del Cuero Cabelludo/tratamiento farmacológico , Dermatosis del Cuero Cabelludo/patologíaRESUMEN
Prostate cancer (PCa), the most common non-skin cancer in men, is a worldwide health concern. Treatment options for aggressive PCa are limited to androgen deprivation therapies (ADT), which are ineffective, with robust diagnostic options also being limited. The prostate specific antigen (PSA) test, for instance, is subject to high levels of false positive results and cannot distinguish between cancer confined to the prostate and aggressive metastatic cancer. As such, additional therapeutic and diagnostic options are urgently required. In recent years, a clear association between activins and prostate cancer has become evident. Activins are members of the TGF-ß superfamily and are responsible for a plethora of physiological processes, including cell proliferation, apoptosis, immune surveillance, embryonic development, and follicle stimulating hormone (FSH) regulation. Activin A normally inhibits cancer development and progression, however, cancer cell growth in high-grade PCa is not inhibited by this protein. The mechanism for this apparent acquired capability to resist activin A-mediated growth inhibition is currently not well understood. Thus, the aim of this review is to analyse the role of activin A in PCa progression and to present mechanisms by which transformed cells may escape its effects. The overarching hypothesis is that insensitivity to the growth inhibitory effects of activin A is an acquired capability in PCa progression. Therefore, local and genetic elements that may be responsible for this change in cellular sensitivity to activin A during cancer progression will be highlighted with a view to identifying potential diagnostic or therapeutic targets.
Asunto(s)
Activinas/fisiología , Neoplasias de la Próstata/fisiopatología , Activinas/uso terapéutico , Proliferación Celular/efectos de los fármacos , Transformación Celular Neoplásica/efectos de los fármacos , Progresión de la Enfermedad , Inhibidores de Crecimiento/fisiología , Humanos , Masculino , MicroARNs/metabolismo , Neoplasias de la Próstata/diagnóstico , Neoplasias de la Próstata/terapiaRESUMEN
Severe bacterial infections such as sepsis and meningitis still kill or severely injure people despite the use of bactericidal antibiotics. Therefore, new strategies for a better therapy are needed. Activin A, a member of the TGF-ß superfamily and its binding protein follistatin (FS) are released by various cell types during acute and chronic inflammatory processes. Until now, a clear definition of conditions in which activin A exerts either its pro- or anti-inflammatory functions is lacking. The activin/FS-system participates in the fine-tuning of the host's inflammatory response upon infectious stimuli. This response is on the one hand necessary for fighting pathogens, but on the other hand can negatively affect the host. This article focuses on the role of activin A and FS in infection and after acute inflammatory stimuli. The therapeutic potentials of blocking or promoting activin actions are discussed.