Transforming Growth Factor-beta Family Research Articles

Exploring the Potential of Wild Olive (Acebuche) Oil as a Pharm-Food to Prevent Ocular Hypertension and Fibrotic Events in the Retina of Hypertensive Mice.

Our laboratoryhas previously described the antioxidant and anti-inflammatory potential of a wild olive (acebuche, ACE) oil against hypertension-associated vascular retinopathies. The current study aims to analyze the antifibrotic effect of ACE oil on the retina of hypertensive mice. Mice are rendered hypertensive by administration of NG-nitro-L-arginine-methyl-ester (L-NAME) and simultaneously subjected to dietary supplementation with ACE oil or a reference extra virgin olive oil (EVOO). Intraocular pressure (IOP) is measured by rebound tonometry, and retinal vasculature/layers are analyzed by fundus fluorescein angiography and optical coherence tomography. Different fibrosis-related parameters are analyzed in the retina and choroid of normotensive and hypertensive mice with or without oil supplementation. Besides preventing the alterations found in hypertensive animals, including increased IOP, reduced fluorescein signal, and altered retinal layer thickness, the ACE oil-enriched diet improves collagen metabolism by regulating the expression of major fibrotic process modulators (matrix metalloproteinases, tissue inhibitors of metalloproteinases, connective tissue growth factor, and transforming growth factor beta family). Regular consumption of EVOO and ACE oil (with better outcomes in the latter) might help reduce abnormally high IOP values in the context of hypertension-related retinal damage, with significant reduction in the surrounding fibrotic process.

P-604 Inhibin B in Low Ovarian Reserve Patients: Correlation With Ovarian Reserve Markers and Oocyte Yield

Abstract Study question Is there a correlation between Inhibin B (InhB) serum levels and oocyte yield after ovarian stimulation (OS) in women with low ovarian reserve? Summary answer InhB presents a positive relationship with oocyte yield during OS in women with AMH<1.1ng/mL. What is known already InhB is produced by granulosa cells in the ovary with the goal of suppressing FSH production. Assay and intercycle variability have been the main limitations affecting specificity and reproducibility of InhB as a marker of ovarian reserve or oocyte yield after OS. This fact is attributed to low specific antibodies for the molecule in previous assays, exhibiting cross-reactivity with other glycoproteins in the transforming growth factor beta family. High specific ELISA assay,measuring bioavailable InhB (bio-InhB), may provide more accurate results, specially important in poor responders, as results may involve clinical decisions on whether or not to proceed with OS. Study design, size, duration Prospective observational study measuring bio-InhB in 72 women with low ovarian reserve, performing OS for IVF/ICSI, at a tertiary referral fertility center, from February 2019 to December 2021. Low ovarian reserve was defined as AMH serum levels <1.1ng/ml (Elecsys, Roche), following Bologna criteria. All patients performed OS for IVF/ICSI in a GnRH-antagonist protocol. Participants/materials, setting, methods On day 2/3 of cycle, before starting OS, AFC, FSH, LH, estradiol, progesterone and AMH (Elecsys, Roche) were measured. Extra serum samples were frozen at -20C for subsequent bio-InhB analysis (AnshLabs, Texas). Ethical approval was obtained (Research Ethics Committee-REFA033c) and informed consent was signed for all participants. Main results and the role of chance Patient characteristics were [Median(IQR)]: age: 39(36-42)years, BMI: 28.51(26.1-30.1) Kg/m2, AFC: 5.5(4-7), FSH:8.23(6.4-12.5) mIU/mL, LH: 6.54(4.51-8.91) mIU/mL, Estradiol: 41.18(28.47-56.44) pg/mL, AMH: 0.64(0.29-0.81)ng/mL, InhB: 62.69(33.78-97.92) pg/mL. Stimulation outcomes were: follicle number on day of trigger (Fdot): 5(3-7), cumulus-oocyte-complexes (COC’s): 3(2-4.5) andmetaphase II oocytes (MII): 3(1-4). Inh-B showed significant positive correlation (Spearman correlation) with AMH (rs = 0.35, p = 0.003), although was better with AFC (rs = 0.43, p < 0.001). Moreover, Inh-B serum levels presented positive association with oocyte yield: Fdot (rs = 0.41, p < 0.001), COC’s (rs = 0.36, p = 0.002) and MII (rs = 0.37, p = 0.002). AUROC analysis was performed to investigate which model predicted better a bad outcome (defined as < =3COC’s after OS) in low ovarian reserve women. No significant benefit was observed when Inh-B was added to AMH+AFC model (AUROC AMH+AFC: 0.757; AUROC AMH+AFC+Inh-B: 0.759, p = 0.843). Limitations, reasons for caution Although clinical assessment was performed in the same centre following the same methodology, inter-observer variability for AFC is a limitation. Besides, fresh AMH serum samples were analysed using Elecsys assay, yet frozen serum samples were shipped to Ansh Lab (Texas) for batched Inh-B analysis. Wider implications of the findings Bio-InhB is correlated to oocyte yield during OS. Although no additional benefit for prediction in women with AMH<1.1ng/mL was observed when added to other currently used markers, future research should explore the utility of bio-inhB on other outcomes associated to ovarian reserve, as embryo quality and ploidy. Trial registration number Not applicable

At the Intersection of Cardiology and Oncology: TGFβ as a Clinically Translatable Therapy for TNBC Treatment and as a Major Regulator of Post-Chemotherapy Cardiomyopathy.

Simple SummarySpecific/targeted therapies have been shown to be effective in the treatment of certain cancers. Unfortunately, there is currently no targeted therapy for the treatment of triple-negative breast cancer (TNBC), which is why this subtype of breast cancer is associated with poor patient prognosis. While there is an immense focus on the development of new therapies, the issue of cardiotoxicity following chemotherapeutic treatment is commonly overlooked, despite its role as a leading cause of mortality in cancer survivors. This review aims to discuss the connection of TGF-β signaling and its role in modulating cardiac fibrosis and remodeling, as well as its role in TNBC tumor progression, cancer stem cell enrichment, chemoresistance and relapse. Together, we highlight the modulation of TGF-β as a method to target two of the greatest causes of morbidity and mortality in breast cancer patients.Triple-negative breast cancer (TNBC) is a subtype of breast cancer that accounts for the majority of breast cancer-related deaths due to the lack of specific targets for effective treatments. While there is immense focus on the development of novel therapies for TNBC treatment, a persistent and critical issue is the rate of heart failure and cardiomyopathy, which is a leading cause of mortality and morbidity amongst cancer survivors. In this review, we highlight mechanisms of post-chemotherapeutic cardiotoxicity exposure, evaluate how this is assessed clinically and highlight the transforming growth factor-beta family (TGF-β) pathway and its significance as a mediator of cardiomyopathy. We also highlight recent findings demonstrating TGF-β inhibition as a potent method to prevent cardiac remodeling, fibrosis and cardiomyopathy. We describe how dysregulation of the TGF-β pathway is associated with negative patient outcomes across 32 types of cancer, including TNBC. We then highlight how TGF-β modulation may be a potent method to target mesenchymal (CD44+/CD24−) and epithelial (ALDHhigh) cancer stem cell (CSC) populations in TNBC models. CSCs are associated with tumorigenesis, metastasis, relapse, resistance and diminished patient prognosis; however, due to plasticity and differential regulation, these populations remain difficult to target and continue to present a major barrier to successful therapy. TGF-β inhibition represents an intersection of two fields: cardiology and oncology. Through the inhibition of cardiomyopathy, cardiac damage and heart failure may be prevented, and through CSC targeting, patient prognoses may be improved. Together, both approaches, if successfully implemented, would target the two greatest causes of cancer-related morbidity in patients and potentially lead to a breakthrough therapy.

Involvement of Transforming Growth Factor Beta Family Genes in Gonadal Differentiation in Japanese Eel, Anguilla japonica, According to Sex-Related Gene Expressions.

The gonochoristic feature with environmental sex determination that occurs during the yellow stage in the eel provides an interesting model to investigate the mechanisms of gonadal development. We previously studied various sex-related genes during gonadal sex differentiation in Japanese eels. In the present study, the members of transforming growth factor beta (TGF-β) superfamily were investigated. Transcript levels of anti-Müllerian hormone, its receptor, gonadal soma-derived factor (amh, amhr2, and gsdf, respectively) measured by real-time polymerase chain reaction (qPCR) showed a strong sexual dimorphism. Transcripts were dominantly expressed in the testis, and their levels significantly increased with testicular differentiation. In contrast, the expressions of amh, amhr2, and gsdf transcripts were low in the ovary of E2-feminized female eels. In situ hybridization detected gsdf (but not amh) transcript signals in undifferentiated gonads. amh and gsdf signals were localized to Sertoli cells and had increased significantly with testicular differentiation. Weak gsdf and no amh signals were detected in early ovaries of E2-feminized female eels. Transcript levels of amh and gsdf (not amhr2) decreased during human chorionic gonadotropin (HCG)-induced spermatogenesis in males. This study suggests that amh, amhr2, and especially gsdf might be involved in the gene pathway regulating testicular differentiation of Japanese eels.

Clinically Translatable Approaches of Inhibiting TGF-β to Target Cancer Stem Cells in TNBC.

Triple-negative breast cancer (TNBC) is a subtype of breast cancer that disproportionally accounts for the majority of breast cancer-related deaths due to the lack of specific targets for effective treatments. In this review, we highlight the complexity of the transforming growth factor-beta family (TGF-β) pathway and discuss how the dysregulation of the TGF-β pathway promotes oncogenic attributes in TNBC, which negatively affects patient prognosis. Moreover, we discuss recent findings highlighting TGF-β inhibition as a potent method to target mesenchymal (CD44+/CD24−) and epithelial (ALDHhigh) cancer stem cell (CSC) populations. CSCs are associated with tumorigenesis, metastasis, relapse, resistance, and diminished patient prognosis; however, due to differential signal pathway enrichment and plasticity, these populations remain difficult to target and persist as a major barrier barring successful therapy. This review highlights the importance of TGF-β as a driver of chemoresistance, radioresistance and reduced patient prognosis in breast cancer and highlights novel treatment strategies which modulate TGF-β, impede cancer progression and reduce the rate of resistance generation via targeting the CSC populations in TNBC and thus reducing tumorigenicity. Potential TGF-β inhibitors targeting based on clinical trials are summarized for further investigation, which may lead to the development of novel therapies to improve TNBC patient prognosis.

Semen Modulates Inflammation and Angiogenesis in the Reproductive Tract of Female Rabbits.

Simple SummaryIn mammals, the expression of regulatory genes is modified by the interaction between semen and the female reproductive tract. This study intends to unveil how mating or insemination with sperm-free seminal plasma, as well as the presence of preimplantation embryos, affects inflammation and angiogenesis in different segments of the reproductive tract of female rabbits. Gene expression of anti-inflammatory cytokines and angiogenesis mediators was analyzed in segmented tracts (cervix to infundibulum) in response to mating and sperm-free seminal plasma infusion. Moreover, the gene expression at different times post-mating was also analyzed. Results showed that gene expression changes were mainly localized in the uterus in the natural mating group, describing a clear temporal variation, while limited to the oviduct in the sperm-free seminal plasma group. These changes suggest an early response in the uterus and late modulation in the oviduct, distinctly demonstrating that semen and seminal plasma, through their interaction with the female reproductive tract, can differentially modulate the expression of anti-inflammatory and angiogenesis mediators.The maternal environment modulates immune responses to facilitate embryo development and ensure pregnancy. Unraveling this modulation could improve the livestock breeding systems. Here it is hypothesized that the exposure of the female rabbit reproductive tract to semen, as well as to early embryos, modulates inflammation and angiogenesis among different tissue segments. qPCR analysis of the gene expression changes of the anti-inflammatory interleukin-10 (IL10) and transforming growth factor beta family (TGFβ1–3) and the angiogenesis mediator vascular endothelial growth factor (VEGF-A) were examined in response to mating or insemination with sperm-free seminal plasma (SP). Reproductive tract segment (cervix to infundibulum) samples were obtained in Experiment 1, 20 h after gonadotropin-releasing hormone (GnRH) stimulation (control), natural mating (NM) or vaginal infusion with sperm-free SP (SP-AI). Additionally, segmented samples were also obtained at 10, 24, 36, 68 or 72 h after GnRH-stimulation and natural mating (Experiment 2). The results of gene expression, analyzed by quantitative PCR, showed that NM effects were mainly localized in the uterine tissues, depicting clear temporal variation, while SP-AI effects were restricted to the oviduct. Changes in anti-inflammatory and angiogenesis mediators indicate an early response in the uterus and a late modulation in the oviduct either induced by semen or preimplantation embryos. This knowledge could be used in the implementation of physiological strategies in breeding systems to face the new challenges on rabbit productivity and sustainability.

Integrated TCGA and GEO analysis showed that SMAD7 is an independent prognostic factor for lung adenocarcinoma.

The lack of effective markers leads to missed optimal treatment times, resulting in poorer prognosis in most cancers. Drosophila mothers against decapentaplegic protein (SMAD) family members are important cytokines in the transforming growth factor-beta family. They jointly regulate the processes of cell growth, differentiation, and apoptosis. However, the expression of SMAD family genes in pan-cancers and their impact on prognosis have not been elucidated. Perl software and R software were used to perform expression analysis and survival curve analysis on the data collected by TCGA, GTEx, and GEO, and the potential regulatory pathways were determined through gene ontology enrichment and kyoto encyclopedia of genes and genomes enrichment analysis. It was found that SMAD7 and SMAD9 expression decreased in lung adenocarcinoma (LUAD), and their expression was positively correlated with survival time. Additionally, SMAD7 could be used as an independent prognostic factor for LUAD. In general, SMAD7 and SMAD9 can be used as prognostic markers of LUAD. Further, SMAD7 is expected to become a therapeutic target for LUAD.

Evaluation of Transforming Growth Factor- β 1 Gene Expression and Polymorphism in Diagnosis of Hepatocellular Carcinoma in HCV-Infected Patients

Background: Transforming growth factor-beta1 (TGF-β1), a member of transforming growth factor beta family, functions as a multi-functional cytokine and plays a key role in cellular growth, proliferation and differentiation. Aim of the work: To evaluate the role of TGF-β1 polymorphisms 509 C>T and TGF-β1 Gene expression in diagnosis of hepatocellular carcinoma (HCC) in cirrhotic Egyptian patients due to hepatitis C virus (HCV). Subjects and methods: Thirty five cirrhotic with HCC patients, thirty cirrhotic without HCC patients and 20 healthy volunteers were enrolled in this study. TGF-β1 gene expression in peripheral blood was quantitated using real-time polymerase chain reaction and molecular study of TGF-β1 509 C>T (rs1800469) polymorphism by Taqman allele discrimination was done for all subjects. Results: Showed that TGF-β1 -509 CT genotype was the most frequent genotype in HCC patients and the most frequent allele was T allele in HCC patients, without significant difference of TGF-β1 -509 polymorphism in the studied groups. TGF-β1 gene expression was significantly higher in HCC patients (mean 3.19±1.8) than in cirrhotic without HCC patients (mean 1.76±0.95) (p T was not associated with the risk of HCC in HCV-cirrhotic patients.

Influence of semen on inflammatory modulators of embryo implantation

Insemination transmits to the female reproductive tract constituents of seminal plasma that target uterine epithelial cells to activate a cascade of inflammatory and immunological changes. Experiments in rodents show seminal factor signalling acts to 'condition' the female immune response to tolerate the conceptus, and to organise molecular and cellular changes in the endometrium to facilitate embryo development and implantation. The active factors in seminal plasma are identified as members of the transforming growth factor-beta family, with the relative balance of active moieties influencing the precise character of the female tract response. Experiments in rodents show that disruption of seminal plasma priming causes foetal growth retardation and changes in placental structure, with long-term consequences for the growth of the neonate. Recent studies indicate a similar physiological function and molecular basis for seminal plasma actions in the pig. In gilts, seminal plasma elicits an endometrial response characterised by recruitment of inflammatory leukocytes and induction of several pro-inflammatory cytokines and cyclo-oxygenase-2. The consequences are evident throughout the pre-implantation period of early pregnancy with altered leukocyte populations and cytokine parameters seen for at least 9 days. Exposure to semen also alters the dynamics in pre-implantation embryo development with an increase in the number of embryos and in their viability. Furthermore seminal plasma influences the temporal kinetics of ovulation, corpus luteum development and steroid production in the ovary. Dissecting the actions of seminal plasma may facilitate development of strategies to ensure maximal fertility and reduce embryo mortality in the pig.

CUB domain-containing protein 1 (CDCP1) binds transforming growth factor beta family members and increase TGF-β1 signaling pathway

CUB domains are most exclusively found in secreted proteins and in a few transmembrane proteins. These domains are approximately 110 amino acids long and have four conserved cysteines that form a β-sandwich fold. CUB domains proteins are involved in a wide range of biological functions. We have shown that CUB domains from Tolloid/BMP1 can bind BMP4 and block BMP signaling in the developing frog embryo. CUB domain-containing protein 1 (CDCP1) is one of the few transmembrane glycoprotein that contains three extracellular CUB domains and regulates anchorage-independent growth and cancer cell migration through activation of Src kinases. In the extracellular space, only a few proteins were found to interact with CDCP1 and at the moment no ligand was found. We demonstrate by using real time protein interaction on BIAcore chip that CDCP1 CUB domains bind directly to TGF-β1 and BMP4. CDCP1 enhances TGF-β1 signaling reporter activity and phosphorylated Smad2 levels but does not modulate BMP signaling pathway. CDCP1 actions on TGF-β/Smad2 signaling are dependent on Smad2 and TGFRI and do not require Src or PKCδ binding. Our findings uncover a new co-receptor for TGF-β1 and bring up new questions on whether CDCP1 cooperates with TGF-β1 to promote cancer progression.

Transforming growth factor-beta family members are regulated during induced luteolysis in cattle

The transforming growth factors beta (TGFβ) are local factors produced by ovarian cells which, after binding to their receptors, regulate follicular deviation and ovulation. However, their regulation and function during corpus luteum (CL) regression has been poorly investigated. The present study evaluated the mRNA regulation of some TGFβ family ligands and their receptors in the bovine CL during induced luteolysis in vivo. On day 10 of the estrous cycle, cows received an injection of prostaglandin F2α (PGF) and luteal samples were obtained from separate groups of cows (n= 4-5 cows per time-point) at 0, 2, 12, 24 or 48 h after treatment. Since TGF beta family comprises more than 30 ligands, we focused in some candidates genes such as activin receptors (ACVR-1A, -1B, -2A, -2B) AMH, AMHR2, BMPs (BMP-1, -2, -3, -4, -6 and -7), BMP receptors (BMPR-1A, -1B and -2), inhibin subunits (INH-A, -BA, -BB) and betaglycan (TGFBR3). The mRNA levels of BMP4, BMP6 and INHBA were higher at 2 h after PGF administration (P<0.05) in comparison to 0 h. The relative mRNA abundance of BMP1, BMP2, BMP3, BMP4, BMP6, ACVR1B, INHBA and INHBB was upregulated up to 12 h post PGF (P<0.05). On the other hand, TGFBR3 mRNA that codes for a reservoir of ligands that bind to TGF-beta receptors, was lower at 48 h. In conclusion, findings from this study demonstrated that genes encoding several TGFβ family members are expressed in a time-specific manner after PGF administration.

Transforming Growth Factor-Beta Family: Advances in Vascular Function and Signaling.

This review includes a comprehensive, but succinct, summary on the essentials of TGF- β structure, family members, receptors, and intracellular mediators. Also provided is a select list of original publications that report novel roles and facets of TGF-β in vascular function and signaling in the contexts of health and disease.

Transcriptome profiling of anti-müllerian hormone treated preantral/small antral mouse ovary follicles.

The predisposition for the initiation of folliculogenesis in mammals including humans is programmed to start at fetal life and continues until reproductive capacity. The follicles grow from a pool of primordial follicles which retain the major functions in the entire reproductive life of a female. Anti-müllerian hormone (AMH), a glycoprotein belonging to the transforming growth factor-beta family, has an inhibitory effect on ovarian follicle development. The key regulatory target genes in primordial follicle development are of paramount importance in reproductive biology of female. A systems biology method was used to find regulatory genes performing critical role in primordial follicle development. A complete in-depth bioinformatics analysis was performed to investigate the changes in transcriptome of preantral to small antral mouse follicles treated for 12 h and 24 h with two different concentrations; 50 and 200 ng/ml of AMH, and thereby identify candidate genes in time and concentration manner. Firstly, we found differentially expressed genes that were time and concentration dependent in response to AMH. The network analysis of these differentially expressed genes provided new candidate genes and pathways associated with inhibitory action of AMH on the primordial follicle development. To further emphasize the function of AMH, the key identified genes’ protein-protein docking was analyzed and found the intracellular and extracellular protein-protein interaction. This study elucidates one of the novel mechanisms of AMH involvement in inhibition of ovarian follicle development which may lead to prolong productive life in female.

Level of Chemerin and Anti-Müllerian Hormone in Egyptian Obese Women with Polycystic Ovarian Syndrome

Background: Chemerin is a newly discovered adipokine that regulates adipocyte development, metabolic function as well as immune function. Anti-Mullerian hormone (AMH) is a dimeric glycoprotein that belongs to the transforming growth factor-beta family. Aim of the study: was to evaluate the serum levels of Chemerin and AMH in one trial to show their possible involvement in the pathogenesis of PCOS and their association with obesity. Subjects and methods: This study was performed on eighty subjects divided into 4 groups: Group I: 20 non-obese control (BMI< 30), Group II: 20 non-obese patient with polycystic ovarian syndrome (BMI< 30), Group III: 20 obese Control (BMI ≥ 30) and Group IV: 20 obese patient with PCOS (BMI ≥ 30). Serum levels of Chemerin and AMH were estimated by ELISA. Results: Results showed a significant increase in serum levels of Chemerin and AMH in (non-obese and obese) PCOS groups when compared to their controls. Results showed also a significant increase in the serum level of Chemerin in obese PCOS group when compared to non-obese PCOS group. While a significant decrease in serum level of AMH in obese PCOS group when compared to non-obese PCOS group. There were a significant positive correlation between Chemerin and AMH in PCOS groups. Conclusion: Chemerin together with AMH may be used as a biomarker for early detection of PCO and Clinical parameters as Infertility and Hyper and rogenism in women with PCOS.

Role and mechanism of AMH in the regulation of Sertoli cells in mice

Sertoli cells produce anti-Müllerian hormone (AMH), a glycoprotein belonging to the transforming growth factor-beta family. AMH mediates the regression of Müllerian ducts in the developing male fetus. However, the role of AMH in the regulation of primary Sertoli cells remains unclear. The present study was designed to investigate the effect of AMH on the viability and proliferation of Sertoli cells, with an additional focus on stem cell factor (SCF). Treatment of Sertoli cells with increasing concentrations of rh-AMH (0, 10, 50, 100, and 800ng/ml) for two days revealed that AMH, at high concentrations, increased apoptosis. These results were confirmed by a significant increase in Caspase-3 and Bax and a decrease in Bcl-2 protein and mRNA expression (P<0.01). Paradoxically, treatment with a low concentration of rh-AMH (10ng/ml), but not higher concentrations (50–800ng/ml), promoted Sertoli cell proliferation, which was verified by an increase in PCNA mRNA (P<0.05). Furthermore, only low concentrations of rh-AMH activated the non-canonical ERK signaling pathway. Similarly, low concentrations of rh-AMH (10–50ng/ml) significantly increased (P<0.05) SCF mRNA and SCF protein levels. These findings indicate that AMH differentially regulates the fate of Sertoli cells in vitro by promoting proliferation at low concentrations and apoptosis at high concentrations. In addition, AMH increased the expression of SCF, an important regulator of Sertoli cell development. Therefore, AMH may play a role in Sertoli cell development.

Amphotericin B–copper (II) complex alters transcriptional activity of genes encoding transforming growth factor-beta family members and related proteins in renal cells

Several chemical modifications have been developed to overcome the toxicity of amphotericin B (AmB). Oxidized forms of AmB (AmB-ox), which may occur in patient's circulation during therapy, are as toxic as AmB. Complexes with copper (II) ions (AmB-Cu2+) have been reported to be less toxic to human cells. Previous studies showed that AmB changed the expression of transforming growth factor-beta (TGF-β). Therefore, the objective of this study was to investigate the influence of AmB and its modified forms on the expression of genes encoding for TGF-β family members and related proteins in renal cells. Human renal proximal tubule cells (RPTEC) were treated with AmB-Cu2+, AmB, or the oxidized form AmB-ox. The expression of TGF-β family members and related genes was determined using oligonucleotide microarrays. TGF-β1 protein level was determined using ELISA method. The mRNA level of TGF-β isoforms, TGF-β receptors and differentiating genes was evaluated by real-time RT-qPCR. AmB-Cu2+ increased the mRNA levels of TGF-β1 and TGF-β2 isoforms and two genes encoding receptors: TGFBR1 and TGFBR2. TGF-β1 protein level in culture medium was not increased after stimulation with AmB-Cu2+. Microarray analysis revealed changes in both pro-fibrotic and anti-fibrotic genes. These results suggest that AmB-Cu2+ may induce repair mechanisms in renal proximal tubule cells via changes in the expression of genes involved in intracellular signaling.

TGF‐beta Signalling and Development of Mouse Midbrain Dopaminergic Neurons and Hindbrain Serotonergic Neurons

Tyrosine hydroxylase (TH) positive, midbrain dopaminergic neurons (mDA) and hindbrain serotonergic neurons (5‐HT) represent clinically important ventral neuronal subpopulations. Dysregulation of mDA has been linked to the development of depression and drug addiction, while their degeneration leads to the characteristic symptoms of Parkinson's disease. Dysfunction of hindbrain 5HT neurons has been associated with several neurological and psychiatric diseases. In previous studies we have shown that members of the transforming growth factor beta family are regulators of development and maintenance of mDA neurons. In this work we aim to understand the role that TGF‐beta signalling plays on the development of mDA and hindbrain 5HT neurons. For this purpose, we have generated a conditional knockout mouse model in which a region of the midbrain and hindbrain, including the mDA and rostral 5HT neurons, lacks the TGF‐beta Receptor II (TGFBR2). This model was generated using the Cre‐lox system by crossing the En1‐Cre line, in which the expression of the recombinase Cre is controlled by the Engrailed 1 promoter, and the TGFBR2‐flox line, in which the TGFBR2 gene is floxed. Through the use of immunohistochemistry on brain cryosections, and counts of TH immunopositive cells we found significant reduced numbers in both substantia nigra pars compacta (SNpc) and ventral tegmental area (VTA) of the mutants at E18 and even at E16. In contrast, at E14 comparable numbers of TH immunopositive mDA neurons in cKO and WT were obtained. Using in situ hybridization we have calculated the volume of Cck and Ahd2 expression at E14 and our results show dramatic loss of Cck and Ahd2 expression. Development of rostral and caudal 5‐HT subpopulations was also affected by loss of TGF‐beta signaling. The number of dorsal raphe, median raphe, and paramedian rahe 5‐HT neurons was significantly reduced in the conditional knock out, compared to the wildtype, accompanied by decreased expression of Pet and Gata2.In order to understand the molecular mechanism by which TGF‐beta acts in this process, we performed a cDNA microarray to analyse the transcriptome of the ventral midbrain of conditional knockout mice and compared it with that of wild type mice. Among the genes differentially regulated by the loss of the TGFBR2, we found genes that fall into the category of receptors, ion transporters, phosphatases and molecular chaperones, among others. Some of the differentially regulated genes have been shown to be implicated in processes like inflammation and endosomal sorting. Future analysis will be focused on understanding the function these genes have during the generation of the midbrain DA neurons, in order to shed some light onto the mechanism by which TGF‐beta acts on these process.Support or Funding InformationDFG

Transforming Growth Factor Beta Family in the Pathogenesis of Meningiomas.

Meningiomas account for 36% of primary brain tumors. The pathogenesis of these tumors is not completely established, hindering development of effective chemotherapy. Numerous studies have identified alterations in several growth factors and receptor kinases that regulate meningioma growth. These may be targets for new therapies. One of these, sometimes overlooked, is the transforming growth factor beta (TGF-β) family of proteins. Its receptors and signaling pathways play a critical role in development or progression of many forms of neoplasia. Evidence suggesting a potential role for TGF-β, bone morphogenetic protein, and their mediators is reviewed. TGF-β inhibition of growth in normal leptomeninges may be lost in neoplasia. Moreover, loss of TGF-β and bone morphogenetic protein signaling components and TGF-β type III receptor likely contribute to the development and/or progression of higher grade meningiomas. Accumulating evidence suggests that derangement of TGF-β family signaling contributes to development and progression of meningiomas. The TGF-β family may represent new targets for chemotherapy and could include inhibitors of kinases activated by TGF-β.

The potential role of transforming growth factor beta family ligand interactions in prostate cancer

The transforming growth factor beta (TGF-β) family plays an important role in embryonic development and control of the cell cycle. Members of the TGF-β family have pleiotropic functions and are involved in both the inhibition and progression of various cancers. In particular, deregulation of the TGF-β family has been associated with prostate cancer, as both a mechanism of disease progression and a possible therapeutic target. This review concentrates on the TGF-βs, activins and inhibins, bone morphogenetic proteins and NODAL and their connection to prostate cancer. Whilst most studies examine the family members in isolation, there are multiple interactions that may occur between members which can alter their function. Such interactions include ligand competition for receptor binding and shared intracellular pathways such as the Mothers against decapentaplegic (SMAD) proteins. Another mechanism for interaction within the TGF-β family is facilitated by their dimeric structure; heterodimers can form which exhibit different functional capabilities to their homodimeric counterparts. The potential formation of TGF-β family heterodimers has not been well examined in prostate cancer. The multiple methods of interrelations between members highlights the need for gross analysis of the TGF-β family and related factors in association with prostate cancer, in order to discover possible future avenues for TGF-β based diagnosis and treatments of the disease. This review describes the role of the TGF-β family of proteins in cancer and, in particular, prostate cancer. After a brief overview, the role of individual members of the family is considered and how these members may be involved in prostate cancer growth is discussed. The review highlights the complex interactions that occur between family members and that may contribute to the progression of prostate cancer.

The effect of Transforming Growth Factor Beta family members on tumor initiating cells in primary liver cancer

The effect of Transforming Growth Factor Beta family members on tumor initiating cells in primary liver cancer