This perspective article proposes that the induction of bone by recombinant human bone morphogenetic proteins (hBMPs), and by the recombinant human transforming growth factor-β3 (hTGF-β3), the latter only in primates, recapitulates embryonic development, whereby large ossicles de novo form in heterotopic intramuscular sites, where several responding cells are available with marked vascular invasion. The induction of bone initiates with the induction of cartilage' anlages recapitulating development. Selected recombinant hBMPs, hBMP-2 and hOP-1 (hBMP-7) on the other hand, fail to induce significant osteoinduction in orthotopic intraskeletal sites in clinical contexts. This review proposes that the failure of significant clinical bone formation in orthotopic sites is because implantation of hBMP-2 and hOP-1, as well as hTGF-β3 in human mandibular sites, does not proceed via recapitulation of embryonic development, ultimately failing the clinical translation of the "bone induction principle". Biologically, a prerogative of the osteogenic proteins of the TGF-β super family, is the heterotopic induction of bone that initiates via recapitulation of embryonic bone development. Delivery of recombinant hBMP-2 and/or hOP-1 into human bony defects fails because the induction of bone is possible only via embryonic development, which does not occur in orthotopic sites, with limited responding cells and vascular supply. The initiation and assembly of the bone/bone-marrow organ follow a multistep molecular and cellular cascades that ultimately morphogenize the assembly of skeletogenesis masterminding ambulation, body erection, masticatory functions, copulation and the preservation of vital organs and tissues such as the marrow and the cerebral hemispheres. Embryologically, bone forms either via mesenchymal osteogenesis or via endochondral osteogenesis. The former route prevalently sculpts the craniomandibulofacial bones by inducing aggregation of targeted mesenchymal cells to condensate in the primordia of the craniofacial skeleton. A critical step is the condensation of mesenchymal cells that forms around vessels, as the vessels guide the formation of bone. Endochondral osteogenesis initiates by firstly constructing cartilage' anlages that developing bone uses as struts to growth and differentiate. The cartilage anlage is an extraordinary conduit that sets into motion molecular and cellular cell-to-cell, cell-to-receptors cross-talking to initiate angiogenesis and capillary invasion within the hypertrophic cartilage, chondrolysis that initiate osteoblastic cellular differentiation and the deposition of bone, osteoid synthesis, bone marrow development and the induction of a complete mineralized bone-bone marrow organ. The assembled constructs are storage of critical ions, several structural proteins such as osteonectins and fibronectins, biological markers of osteoblast' secretion and activity, such as osteocalcin, together with an array of extraordinary morphogen initiators that de novo set into motion the molecular and cellular cascades inducing bone in heterotopic sites recapitulating embryonic development. In evolutionary molecular biology contexts however, the pleiotropic activities of both proteins' family and the induction of bone formation in heterotopic sites are developmental, and thus not suitable to induce bone when recombinant morphogens are singly implanted in orthotopic skeletal defects, the latter lacking the developmental biological platform.

Adipose tissue fibrosis, characterized by abnormal extracellular matrix deposition within adipose tissue, signifies a crucial indicator of adipose tissue malfunction, potentially leading to organ tissue dysfunction. Various factors, including a high-fat diet, non-alcoholic fatty liver disease, and insulin resistance, coincide with adipose tissue fibrosis. MicroRNAs (miRNAs) represent a class of small non-coding RNAs with significant influence on tissue fibrosis through diverse signaling pathways. For instance, in response to a high-fat diet, miRNAs can modulate signaling pathways such as TGF-β/Smad, PI3K/AKT, and PPAR-γ to impact adipose tissue fibrosis. Furthermore, miRNAs play roles in inhibiting fibrosis in different contexts: suppressing corneal fibrosis via the TGF-β/Smad pathway, mitigating cardiac fibrosis through the VEGF signaling pathway, reducing wound fibrosis via regulation of the MAPK signaling pathway, and diminishing fibrosis post-fat transplantation via involvement in the PDGFR-β signaling pathway. Notably, the secretome released by miRNA-transfected adipose-derived stem cells facilitates targeted delivery of miRNAs to evade host immune rejection, enhancing their anti-fibrotic efficacy. Hence, this study endeavors to elucidate the role and mechanism of miRNAs in adipose tissue fibrosis and explore the mechanisms and advantages of the secretome released by miRNA-transfected adipose-derived stem cells in combating fibrotic diseases.

Neferine is a bisbenzylisoquinoline alkaloid derived from the seed embryo of Nelumbo nucifera, a traditional Chinese medicine. It has been extensively studied for its therapeutic potential in various disease models. Extensive research has highlighted its diverse pharmacological activities, including antitumor, anti‑inflammatory, anti‑fibrosis, anti‑oxidative stress, anti‑platelet aggregation and anti‑arrhythmic effects. The present review, however, focuses on the anti‑inflammatory properties of neferine, emphasizing its fundamental mechanisms as demonstrated in both in vivo and in vitro studies. By critically evaluating its effect on inflammation and the underlying pathways, this review aims to provide a comprehensive understanding of the potential of neferine in the management of inflammatory diseases. Furthermore, it seeks to establish a foundational framework for the future development of neferine as a novel therapeutic agent for inflammatory conditions.

Gremlin-1 (GREM1), a well-known bone morphogenetic protein (BMP) antagonist, is highly expressed in various malignant tumours. However, the specific role of GREM1 in tumours remains controversial and may be attributed to the heterogeneity and complexity of the tumour microenvironment (TME). It is currently believed that GREM1 regulates the complex landscape of the TME, primarily by antagonising BMP signalling or BMP-independent pathways. Both GREM1 and BMP play dual roles in tumour progression. Therefore, the mutual crosstalk between tumour cells and tumour-associated fibroblasts and the regulation of various secreted factors in the TME affect the secretion level of GREM1, which in turn regulates the amplitude balance between GREM1 and BMP, affecting tumour progression. The inhibition of GREM1 activity in the TME can disrupt this amplitude balance and prevent the formation of a tumour-supportive microenvironment, demonstrating that GREM1 is a potential therapeutic target. In this study, we reviewed the specific signalling pathways via which GREM1 in the TME regulates epithelial-mesenchymal transition, construction of the tumour immune microenvironment, and maintenance of tumour cell stemness via BMP-dependent and BMP-independent regulation, and also summarised the latest clinical progress of GREM1.

HNSCC includes nasopharyngeal, laryngeal and oral cancers, and its pathogenesis is influenced by various factors. As an essential part of the ubiquitin (Ub)-proteasome system (UPS), deubiquitinating enzymes (DUBs) maintain the homeostasis of Ub molecules and influence the physiological functions of cells and disease processes by removing ubiquitinated proteins. Accumulating evidence has confirmed that the aberrant expression of DUBs is involved in cell proliferation, metastasis, and apoptosis during the development of HNSCC, with some acting as oncogenes and others as tumor-suppressor genes. In this review, the DUBs implicated in HNSCC were summarized and the mechanisms underlying abnormal DUBs expression in signaling pathways were discussed. In addition, given the important role of DUBs in tumorigenesis, recent studies were reviewed and agonists and inhibitors of DUBs were summarized to identify more effective therapeutic strategies.

The transforming growth factor-β (TGF-β) signaling pathway is involved in various cellular functions, including immunological response, extracellular matrix formation, differentiation, growth and development, and cell cycle regulation. The TGF β receptor type 1 (TGF-βR1) has emerged as a key component of this pathway, exhibiting significant overexpression in diverse malignancies, including hepatocellular carcinoma, gastric cancer, breast cancer, and colon cancer. Multiple therapeutic targets have been identified for the TGF-β signaling pathway, encompassing antibodies, ligand traps, vaccines, antisense oligonucleotides, and small-molecule TGF-βR1 kinase inhibitors. This review delineates the structural and functional characteristics of the small-molecule TGF-βR1 kinase inhibitors. The inhibitors discussed herein are categorized based on shared pharmacophoric features, notably a five-membered heterocyclic ring linked to three distinct features (R1, R2, and R3). These features interact with amino acids within the selectivity pocket, hinge region, or solvent-exposed area, respectively. These insights contribute to a clearer understanding of the structural requirements for selective TGF-βR1 inhibition. The presented findings in this review article offer a valuable foundation for future drug discovery efforts targeting the TGF-β signaling pathway.

Biglycan (BGN) is a small proteoglycan rich in leucine, which plays a crucial role in the excessive production of extracellular matrix (ECM) and its association with fibrosis across various organs. Nevertheless, the precise contribution of BGN to intestinal fibrosis remains undisclosed. This study aimed to investigate the role and mechanism of BGN in intestinal fibrosis.

Human Crohn's disease (CD) tissue samples were obtained from patients with Crohn's disease who underwent surgical resection of the intestine and were categorized as stenotic/nonstenotic regions. A dextran sodium sulfate (DSS)-induced mouse model of intestinal fibrosis was established. Bgn-/0 (BGN KO) mice and primary human intestinal fibroblasts were applied for the study of experimental fibrosis. Coimmunoprecipitation, immunofluorescence staining, western blot, and qRT-PCR were conducted to identify the regulatory effects of BGN on bone morphogenetic protein-7 (BMP-7) expression and intesinal fibrosis.

In both human CD samples and the DSS-induced mouse model of intestinal fibrosis, we observed a significant upregulation of BGN in areas activated by fibrosis. The genetic deletion of BGN resulted in the alleviation of intestinal fibrosis in mice administered DSS. The knockdown of BGN through siRNA significantly attenuated TGF-β1-induced ECM deposition and fibroblastic activation in primary human intestinal fibroblasts. Mechanistically, BGN directly interacted with and negatively regulated the anti-fibrotic protein BMP-7. Rescue experiments demonstrated that BGN facilitated intestinal fibrosis by modulating Smad1/5/8 phosphorylation and activating ECM deposition.

Our data indicate that BGN deficiency inhibits intestinal fibrosis through activation of the BMP-7-Smad1/5/8 signaling pathway. BGN and BMP-7 may become new biomarkers of intestinal fibrosis and novel targets for disease prevention and treatment.

Pathological fibrosis, the excessive deposition of extracellular matrix and tissue stiffening that causes progressive organ dysfunction, underlies diverse chronic diseases. The fibrotic microenvironment is driven by the dynamic microenvironmental interaction between various cell types; macrophages and fibroblasts play central roles in fibrotic disease initiation, maintenance, and progression. Macrophage functional plasticity to microenvironmental stimuli modulates fibroblast functionality by releasing pro-inflammatory cytokines, growth factors, and matrix remodeling enzymes that promote fibroblast proliferation, activation, and differentiation into myofibroblasts. Activated fibroblasts and myofibroblasts serve as the fibrotic effector cells, secreting extracellular matrix components and initiating microenvironmental contracture. Fibroblasts also modulate macrophage function through the release of their own pro-inflammatory cytokines and growth factors, creating bidirectional crosstalk that reinforces the chronic fibrotic cycle. The intricate interplay between macrophages and fibroblasts, including their secretomes and signaling interactions, leads to tissue damage and pathological loss of tissue function. In this review, we examine macrophage-fibroblast reciprocal dynamic interactions in pathological fibrotic conditions. We discuss the specific lineages and functionality of macrophages and fibroblasts implicated in fibrotic progression, with focus on their signal transduction pathways and secretory signalling that enables their pro-fibrotic behaviour. We then finish with a set of recommendations for future experimentation with the goal of developing a set of potential targets for anti-fibrotic therapeutic candidates. Understanding the cellular interactions between macrophages and fibroblasts provides valuable insights into potential therapeutic strategies to mitigate fibrotic disease progression.

The TGF-β superfamily plays a pivotal role in a wide array of cellular processes, including cell proliferation, differentiation, apoptosis, and migration. It is also critically involved in ovarian development and the pathogenesis of various diseases. Within the ovary, follicles act as the primary functional units, housing numerous members of the TGF-β superfamily that regulate follicular development and, consequently, overall ovarian function. Dysregulation of the TGF-β signaling pathway is associated with reproductive disorders and the development of ovarian diseases in female mammals, such as polycystic ovary syndrome (PCOS), premature ovarian aging, ovarian insufficiency, and ovarian cancer. This article highlights the significant contributions of key TGF-β signaling pathway members to follicular development and ovarian disease progression, aiming to deepen the understanding of TGF-β signaling's critical role in reproductive health.

The development of new artificial biomaterials for bone defect repair is an ongoing area of clinical research. Metal ions such as zinc, copper, magnesium, calcium, strontium, silver, and cerium play various roles in bone tissue regeneration in the human body and possess a range of biochemical functions. Studies have demonstrated that appropriate concentrations of these metal ions can promote osteogenesis and angiogenesis, inhibit osteoclast activity, and deter bacterial infections. Researchers have incorporated metal ions into biomaterials using various methods to create artificial bone materials with enhanced osteogenic and antibacterial capabilities. In addition to the osteogenic properties of all the aforementioned metal ions, Zn, Sr, and Ce can indirectly promote osteogenesis by inhibiting osteoclast activity. Cu, Mg, and Sr significantly enhance angiogenesis, while the antibacterial properties of Zn, Cu, Ag, and Ce can reduce the likelihood of infection and inflammation caused by implanted materials. This paper reviews the mechanisms through which metal ions promote bone tissue growth and improve the antibacterial activity of biomaterials. It also summarizes common loading methods on the surface of biomaterials with different metals and highlights the potential clinical applications of these new artificial bone materials.

This study aimed to identify genomic regions associated with prolificacy in Santa Inês sheep raised in tropical conditions. The prolificacy of the dam was defined as single (only one lamb born per ewe per lambing) or multiple (more than one animal born per ewe per lambing). After quality control of phenotypic data, 1584 lambing records of 715 females occurred between the years 2000 and 2018 were used. The animals were genotyped with the OvineSNP50 BeadChip panel (Illumina Inc.). After quality control of genomic data, information of 46,714 SNPs and 388 samples and females was used for the subsequent analyses. The single-step GWAS (ssGWAS) methodology was used to estimate the effects of genetic markers and their association with the prolificacy. A total of 21 windows of 10 adjacent SNPs that explained at least 0.5% of the additive genetic variance for prolificacy were identified. In such regions, genes associated with different reproductive functions in the female were found: CACNA1E, NTRK1, PLCH1, SMAD3, CENPF, TOPBP1, IL33, DRD2, MID1, HCCS, and ARHGAP6. Some candidate regions related to prolificacy harbor genes that were not previously described and genes without known functions. These results can help to identify genes associated with prolificacy and could be used in genomic reproductive studies on prolificacy, as well as in the selection of the most prolific ewes in the population.

PTEN-induced kinase-1 (PINK1) is a crucial player in selective clearance of damaged mitochondria via the autophagy-lysosome pathway, a process termed mitophagy. Previous studies on PINK1 mainly focused on its post-translational modifications, while the transcriptional regulation of PINK1 is much less understood. Herein, we reported a novel mechanism in control of PINK1 transcription by SMAD Family Member 3 (SMAD3), an essential component of the transforming growth factor beta (TGFβ)-SMAD signaling pathway. First, we observed that mitochondrial depolarization promotes PINK1 transcription, and SMAD3 is likely to be the nuclear transcription factor mediating PINK1 transcription. Intriguingly, SMAD3 positively transactivates PINK1 transcription independent of the canonical TGFβ signaling components, such as TGFβ-R1, SMAD2 or SMAD4. Second, we found that mitochondrial depolarization activates SMAD3 via PINK1-mediated phosphorylation of SMAD3 at serine 423/425. Therefore, PINK1 and SMAD3 constitute a positive feedforward loop in control of mitophagy. Finally, activation of PINK1 transcription by SMAD3 provides an important pro-survival signal, as depletion of SMAD3 sensitizes cells to cell death caused by mitochondrial stress. In summary, our findings identify a non-canonical function of SMAD3 as a nuclear transcriptional factor in regulation of PINK1 transcription and mitophagy and a positive feedback loop via PINK1-mediated SMAD3 phosphorylation and activation. Understanding this novel regulatory mechanism provides a deeper insight into the pathological function of PINK1 in the pathogenesis of neurodegenerative diseases such as Parkinson's disease.

Platelet-rich plasma (PRP) is a promising regenerative therapy due to its simplicity, clinical application, safety, and ability to promote angiogenesis. It utilizes various angiogenic growth factors in platelets, including platelet-derived growth factor (PDGF), transforming growth factor-β (TGF-β), insulin-like growth factor-1 (IGF-1), vascular endothelial growth factor (VEGF), and epidermal growth factor (EGF), which are integral to the tissue repair. Critical limb ischemia (CLI) is a major symptom of peripheral arterial disease (PAD), and PRP therapy aims to improve blood circulation to the distal limb through the development of blood vessels. This review focuses on the extensive research on the molecular mechanisms of PRPs in treating CLI. A comprehensive search was conducted on Web of Science, PubMed, Google Scholar, and Scopus to find studies published during PRP therapy in critical limb ischemia up to June 2024. Current studies reveal that PRP composition varies by case, affecting preparation methods, storage duration, storage methods, and interaction with other materials. PRP-derived growth factors have shown promising results in treating CLI, but well-controlled human research is scarce despite positive animal studies.

The neural crest is a highly plastic stem cell population that represents an exception to the germ layer theory. Despite being of ectodermal origin, cranial neural crest cells can differentiate into skeletal derivatives typically formed by mesoderm. Here, we report that SMAD2/3-mediated transforming growth factor β (TGF-β) signaling enhances neural crest developmental potential in the chicken embryo. Our results show that TGF-β signaling modulates neural crest axial identity and directly controls the gene circuits that support skeletal differentiation. Cooperation between TGF-β and low levels of WNT signaling in the embryonic head activates cranial-specific cis-regulatory elements. Activation of TGF-β signaling reprogrammed trunk neural crest cells into adopting an anterior identity and led to the development of an improved protocol for the generation of human cranial neural crest cells. Our findings indicate TGF-β signaling is required for the specification of cranial neural crest cells, endowing them with the potential to give rise to the craniofacial skeleton.

Cancer persists as a ubiquitous global challenge despite the remarkable advances. It is caused by uncontrolled cell growth and metastasis. The Transforming Growth Factor-beta (TGF-β) signaling pathway is considered a primary regulator of various normal physiological processes in the human body. Recently, factors determining the nature of TGF-β response have received attention, specifically its signaling pathway which can be an attractive therapeutic target for various cancer treatments. The TGF-β receptor is activated by its ligands and undergoes transduction of signals via canonical (SMAD dependent) or non-canonical (SMAD independent) signaling pathways regulating several cellular functions. Furthermore, the cross talk of the TGF-β signaling pathway cross with other signaling pathways has shown the controlled regulation of cellular functions. This review highlights the cross talk between various major signaling pathways and TGF-β. These signaling pathways include Wnt, NF-κB, PI3K/Akt, and Hedgehog (Hh). TGF-β signaling pathway has a dual role at different stages. It can suppress tumor formation at early stages and promote progression at advanced stages. This complex behaviour of TGF-β has made it a promising target for therapeutic interventions. Moreover, many strategies have been designed to control TGF-β signaling pathways at different levels, inhibiting tumor-promoting while enhancing tumor-suppressive effects, each with unique molecular mechanisms and clinical implications. This review also discusses various therapeutic inhibitors including ligand traps, small molecule inhibitors (SMIs), monoclonal antibodies (mAbs), and antisense oligonucleotides which target specific components of TGF-β signaling pathway to inhibit TGF-β signaling and are studied in both preclinical and clinical trials for different types of cancer. The review also highlights the prospect of TGF-β signaling in normal physiology and in the case of dysregulation, TGF-β inhibitors, and different therapeutic effects in cancer therapy along with the perspective of combinational therapies to treat cancer.

Shockwave-induced traumatic brain injury (TBI) results in the onset of post-traumatic stress disorder (PTSD), triggered either by the TBI itself or other stressors. However, the interplay and underlying mechanisms of how these factors synergistically induce PTSD remain inadequately elucidated. Here, mice in the TBI (induced by biological shock tube blast injury) and PTSD (induced by single prolonged stress method) groups both displayed symptoms of PTSD behaviors, with the TBI+PTSD (composite model) group exhibiting more severe manifestations. The result of snRNA-seq demonstrated a noticeable increase in the population of Gabra6+ neurons in the prefrontal cortex region of mice in the TBI+PTSD group. Knocking down cortical Gabra6 mitigated PTSD-related behavioral outcomes. Mechanistically, the Smad3/4 complex activation led to the upregulation of Gabra6 expression in cortical neurons. Interaction of Gabra6 with Homer1 activated downstream cAMP signaling pathways. Homer1KO-Nestin mice show reduced susceptibility to PTSD. Subsequently, the efficacy of monoclonal antibody intervention at the 218 site of Gabra6 in ameliorating PTSD development is verified. This study suggests that TBI and stressors act as independent components in PTSD development, with Gabra6+ neurons pivotal in synergistically facilitating PTSD formation. Strategies geared toward minimizing exposure to singular or combined stressors may effectively diminish the risk of developing PTSD.

Transforming growth factor-β (TGF-β) superfamily plays an important role in tumor progression and metastasis. Activin A receptor type 1C (ACVR1C) is a TGF-β type I receptor that is involved in tumorigenesis through binding to different ligands.

To evaluate the correlation between single nucleotide polymorphisms (SNPs) of ACVR1C and susceptibility to esophageal squamous cell carcinoma (ESCC) in Chinese Han population.

In this hospital-based cohort study, 1043 ESCC patients and 1143 healthy controls were enrolled. Five SNPs (rs4664229, rs4556933, rs77886248, rs77263459, rs6734630) of ACVR1C were assessed by the ligation detection reaction method. Hardy-Weinberg equilibrium test, genetic model analysis, stratified analysis, linkage disequilibrium test, and haplotype analysis were conducted.

Participants carrying ACVR1C rs4556933 GA mutant had significantly decreased risk of ESCC, and those with rs77886248 TA mutant were related with higher risk, especially in older male smokers. In the haplotype analysis, ACVR1C Trs4664229Ars4556933Trs77886248Crs77263459Ars6734630 increased risk of ESCC, while Trs4664229Grs4556933Trs77886248Crs77263459Ars6734630 was associated with lower susceptibility to ESCC.

ACVR1C rs4556933 and rs77886248 SNPs were associated with the susceptibility to ESCC, which could provide a potential target for early diagnosis and treatment of ESCC in Chinese Han population.

Mesenchymal stem cells (MSCs) are multipotent stem cells that can exert immunomodulatory capacity upon stimulation with pro-inflammatory cytokines. Our previous work has identified Cullin 4B (CUL4B), a scaffold protein in the CUL4B-RING E3 ligase (CRL4B) complex, as a key regulator in the differentiation of MSCs. Here, we demonstrate the critical role of CUL4B in regulating the immunosuppressive function of MSCs. When stimulated with pro-inflammatory cytokines, MSCs lacking CUL4B display enhanced immunosuppressive capacity, which is mediated by the elevated inducible nitric oxide synthase (iNOS). TGF-β signaling can suppress iNOS by inhibiting its transcription as well as promoting its protein degradation. We show that the CRL4B complex cooperates with PRC2 complex and HDACs to repress transcription of Dlx1 and Pmepa1, two inhibitors of TGF-β signaling, leading to decreased expression and accelerated degradation of iNOS. Our study unveils the CRL4B complex as a potential therapeutic target in promoting the immunosuppressive capacity of MSCs.

Atezolizumab plus bevacizumab has shown promising efficacy in advanced mucosal melanoma in the multi-centre phase II study. This report updates 3-year survival outcomes and multi-omics analysis to identify potential response biomarkers.

Forty-three intention-to-treat (ITT) patients received intravenous administration of atezolizumab and bevacizumab every 3 weeks. Available samples underwent whole exome sequencing, transcriptome sequencing and targeted bisulphite sequencing to assess correlations with clinical outcomes.

With a median follow-up of 40.3 months, the median overall survival (mOS) was 23.7 months (95% confidence interval [CI], 15.1-34), and the 3-year OS rate was 28.7% (95% CI, 17.6%-46.8%). Patients with upper site melanoma exhibited longer progression-free survival (PFS), higher tumour neoantigen burden (TNB) and greater copy number variations (CNVs) burden compared to those with lower site melanoma. NRAS mutations were associated with enhanced angiogenesis, with five of six patients achieving partial response. Inflammatory cell infiltration, angiogenic status and activation of the SMAD2 and p38 MAPK pathways may be prognostic indicators.

This 3-year updated analysis confirms the sustained efficacy of atezolizumab in combination of bevacizumab in patients with advanced mucosal melanoma. Inflammatory cell infiltration and angiogenic status were associated with therapeutic response. Furthermore, mucosal melanoma of upper site and NRAS mutation appear to be good predictors of response to immune checkpoint inhibitor and anti-angiogenic combination treatment. Targeting SMAD2 and p38 MAPK pathways may further improve the outcome of mucosal melanoma.

3-year follow-up study confirmed the therapeutic efficacy of atezolizumab combined with bevacizumab Tumors in the upper site and NRAS mutations are more sensitive to treatment Inflammatory cell infiltration, angiogenic status, and activation of the SMAD2 and p38 MAPK pathways may be prognostic indicators.

Colorectal Cancer (CRC) is the third most common cancer worldwide, and the occurrence and development of CRC are influenced by the molecular biology characteristics of CRC, especially alterations in key signaling pathways. The transforming growth factor-β (TGF-β) plays a crucial role in cellular growth, differentiation, migration, and apoptosis, with SMAD4 protein serving as a key transcription factor in the TGF-β signaling pathway, thus playing a significant role in the onset and progression of CRC. CRC is one of the malignancies with a high mortality rate worldwide. Despite significant research progress in recent years, especially regarding the role of SMAD4, its dual role in the early and late stages of tumor progression has promoted further discussion on its complexity as a therapeutic target, highlighting the urgent need for a deeper analysis of its role in CRC. This review aims to explore the function of SMAD4 protein in CRC and its potential as a therapeutic target.

This population-based cohort study aimed to evaluate the risk of osteoporosis and fractures associated with higher-potency statin use compared to lower-potency statin use in patients with stroke, using data from the Health Insurance and Review Assessment database of South Korea (2010-2019). Patients who received statin within 30 days after hospitalization for a new-onset stroke (n = 276,911) were divided into higher-potency (n = 212,215, 76.6%) or lower-potency (n = 64,696, 23.4%) statin initiation groups. The primary outcome was a composite of osteoporosis and osteoporotic fractures. Secondary outcomes were individual components of the primary outcome, including osteoporosis, vertebral fracture, hip fracture, and non-hip non-vertebral fracture. Cox proportional hazard models weighted by standardized morbidity ratios were used to estimate hazard ratios (HRs) with 95% confidence intervals (CIs). The risk of the composite outcome (HR 0.95, 95% CI 0.93-0.97), osteoporosis (0.93, 0.90-0.96), vertebral fracture (0.95, 0.91-0.99), and hip fracture (0.89, 0.84-0.95) were significantly lower in higher-potency statin users, while the risk for non-hip non-vertebral fracture was not significant (0.98, 0.95-1.02). The use of higher-potency statins compared to lower-potency statins was associated with a lower risk of osteoporosis, vertebral fracture, and hip fracture in patients with stroke.

Epithelial-to-mesenchymal transitions (EMT) and unjamming transitions provide two distinct pathways for cancer cells to become invasive, but it is still unclear to what extent these pathways are connected. Here, we addressed this question by performing 3D spheroid invasion assays on epithelial-like (A549) and mesenchymal-like (MV3) cancer cell lines in collagen-based hydrogels, where we varied both the invasive character of the cells and matrix porosity. We found that the onset time of invasion was correlated with the matrix porosity and vimentin levels, while the spheroid expansion rate correlated with MMP1 levels. Spheroids displayed solid-like (non-invasive) states in small-pore hydrogels and fluid-like (strand-based) or gas-like (disseminating cells) states in large-pore hydrogels or for mesenchymal-like cells. Our findings are consistent with different unjamming states as a function of cell motility and matrix confinement predicted in recent models for cancer invasion, but show that cell motility and matrix confinement are coupled via EMT-related matrix degradation.

Globally, osteoarthritis is a common and highly disabling disease that places a heavy burden on society and medical systems. The role of biomechanical factors in the development of osteoarthritis has gradually received more attention. As a key biomechanical stimulus, fluid shear force is becoming the focus of research for its dual role in maintaining cartilage health and disease progression. This paper conducts an in-depth discussion on the mechanism of fluid shear force in osteoarthritis and its impact on the disease process, aiming to reveal how fluid shear stress affects the development of osteoarthritis by regulating the physiological function and signal transduction pathways of chondrocytes.

Fibrosis is defined by the excessive accumulation of extracellular matrix (ECM) and constitutes a central pathophysiological process that underlies tissue dysfunction, across organs, in multiple chronic diseases and during aging. Myocardial fibrosis is a key contributor to dysfunction and failure in numerous diseases of the heart and is a strong predictor of poor clinical outcome and mortality. The excess structural and matricellular ECM proteins deposited by cardiac fibroblasts, is found between cardiomyocytes (interstitial fibrosis), in focal areas where cardiomyocytes have died (replacement fibrosis), and around vessels (perivascular fibrosis). Although myocardial fibrosis has important clinical prognostic value, access to cardiac tissue biopsies for histological evaluation is limited. Despite challenges with sensitivity and specificity, cardiac magnetic resonance imaging (CMR) is the most applicable diagnostic tool in the clinic, and the scientific community is currently actively searching for blood biomarkers reflecting myocardial fibrosis, to complement the imaging techniques. The lack of mechanistic insights into specific pro- and anti-fibrotic molecular pathways has hampered the development of effective treatments to prevent or reverse myocardial fibrosis. Development and implementation of anti-fibrotic therapies is expected to improve patient outcomes and is an urgent medical need. Here, we discuss the importance of the ECM in the heart, the central role of fibrosis in heart disease, and mechanistic pathways likely to impact clinical practice with regards to diagnostics of myocardial fibrosis, risk stratification of patients, and anti-fibrotic therapy.

Phacoemulsification combined with intraocular lens implantation is the primary treatment for cataract. Although this treatment strategy benefits patients with cataracts, posterior capsule opacification (PCO) remains a common complication that impairs vision and affects treatment outcomes. The pathogenesis of PCO is associated with the proliferation, migration, and fibrogenesis activity of residual lens epithelial cells, with epithelial-mesenchymal transition (EMT) serving as a key mechanism underlying the condition. Transforming growth factor-beta 2 (TGF-β2) is a major promotor of EMT, thereby driving PCO development. Most studies have shown that drugs and miRNAs mitigate EMT by inhibiting, clearing, or eliminating LECs. In addition, targeting EMT-related signaling pathways in TGF-β2-stimulated LECs has garnered attention as a research focus. This review highlights potential treatments for PCO and details the mechanisms by which drugs and miRNAs counter EMT.

Cryptococcus neoformans, the causative agent of cryptococcosis and a representative of the Basidiomycota phylum of Fungi, is a valuable model for our understanding of eukaryotic/fungal biology. Negative feedback is a well-documented mechanism across Eukarya to regulate developmental transitions. Here, we describe a repressor of the yeast-to-hypha transition, Ref1, which completes a negative feedback loop driven by the master regulator of hyphal morphogenesis, Znf2, during sexual development. Alternative transcription of Ref1, driven by Znf2, produces a functionally distinct Ref1 isoform. Isoform-specific capacity for phase separation imparts this functional distinction, making Ref1 a stronger repressor and more vulnerable to proteolytic degradation. The multimodal nature of Ref1 provides versatility that allows cells to fine-tune Ref1 activity to suit developmental context. This work reveals a mechanism by which phase separation allows a transcriptional program to tailor its own repression to guide an organism through morphological transition.

The relationship between statin treatment and fracture risk is still controversial, especially in in patients with cardiovascular diseases (CVDs). We aim to determine whether statin therapy affects the occurrence of fractures in the general US population and in patients with CVDs.

Epidemiological data of this cross-sectional study were extracted from the National Health and Nutrition Examination Survey (NHANES, 2001-2020, n = 9,893). Statins records and fracture information were obtained from the questionnaires. Weighted logistic regressions were performed to explore the associations between statin and the risk of fracture.

Statin use was found to be associated with reduced risk of fracture mainly in male individuals aged over 50 years old and taking medications for less than 3 years, after adjusted for confounders including supplements of calcium and vitamin D. The protective effects were only found in subjects taking atorvastatin and rosuvastatin. We found null mediation role of LDL-C and 25(OH)D in such effects. Statin was found to reduce fracture risk in patients with cardiovascular diseases (CVDs, OR: 0.4366, 95%CI: 0.2664 to 0.7154, P = 0.0014), and in patients without diabetes (OR: 0.3632, 95%CI: 0.1712 to 0.7704, P = 0.0091).

Statin showed advantages in reducing risk of fracture in male individuals aged over 50 years old and taking medications for less than 3 years. More research is needed to determine the impact of gender variations, medication duration, and diabetes.

Bone morphogenetic protein 3b (BMP3b), also known as growth differentiation factor 10 (GDF10), is a non-osteogenic BMP highly expressed in the skeleton. Although in vitro studies have shown that BMP3b suppresses osteoblast differentiation, the physiological role of BMP3b in regulating bone mass in vivo remains unknown. Here, we show that BMP3b deletion in mice leads to a high bone mass phenotype via an unexpected novel mechanism involving de-repression of canonical BMP/Smad signaling. BMP3b null mice were viable, and exhibited no significant difference in body size compared to wildtype control. Trabecular bone parameters assessed by histomorphometry and μCT, revealed a significant increase in bone volume and bone mineral density. Expression of osteoblast-differentiation genes were elevated in bone tissue of BMP3b null mice, whereas expression of osteoclast-related genes remained unchanged. Consistent with this, Bmp3b was highly expressed in osteoblasts relative to osteoclast cells. Ex-vivo culture of primary bone marrow mesenchymal stem cells (BMSCs) and primary bone marrow-derived osteoclasts revealed that inactivation of BMP3b enhances osteogenesis without affecting osteoclastogenesis. Mechanistically, we found that BMP3b suppressed BMP4-induced Smad1/5 phosphorylation and inhibited the activity of a BMP4-driven Id-1 luciferase reporter. Protein-protein interaction assays revealed that BMP3b competitively interfered with the association of BMP4 and BMP type I receptors. These findings suggest that BMP3b regulates bone mass by acting as a BMP receptor antagonist. Thus, maintenance of bone mass involves antagonism of canonical BMP/Smad signaling by a member of the BMP family.

Radiotherapy is a pivotal intervention for cancer patients, significantly impacting their treatment outcomes and survival prospects. Nevertheless, in the course of treating those with abdominal, pelvic, or retroperitoneal malignant tumors, the procedure inadvertently exposes adjacent intestinal tissues to radiation, posing risks of radiation-induced enteropathy upon reaching threshold doses. Stem cells within the intestinal crypts, through their controlled proliferation and differentiation, support the critical functions of the intestinal epithelium, ensuring efficient nutrient absorption while upholding its protective barrier properties. Intestinal stem cells (ISCs) regulation is intricately orchestrated by diverse signaling pathways, among which are the WNT, BMP, NOTCH, EGF, Hippo, Hedgehog and NF-κB, each contributing to the complex control of these cells' behavior. Complementing these pathways are additional regulators such as nutrient metabolic states, and the intestinal microbiota, all of which contribute to the fine-tuning of ISCs behavior in the intestinal crypts. It is the harmonious interplay among these signaling cascades and modulating elements that preserves the homeostasis of intestinal epithelial cells (IECs), thereby ensuring the gut's overall health and function. This review delves into the molecular underpinnings of how stem cells respond in the context of radiation enteropathy, aiming to illuminate potential biological targets for therapeutic intervention. Furthermore, we have compiled a summary of several current treatment methodologies. By unraveling these mechanisms and treatment methods, we aspire to furnish a roadmap for the development of novel therapeutics, advancing our capabilities in mitigating radiation-induced intestinal damage.

Age-related susceptibility to sepsis and endotoxemia is poorly defined, although hyperactivation of the immune system and the expansion of the visceral adipose as an immunological reservoir are underlying features. Macrophages from older organisms exhibit substantial changes, including chronic NLRP3 inflammasome activation, genomic remodeling and a dysfunctional, amplified inflammatory response upon new exposure to pathogen. However, the mechanisms by which old macrophages maintain their inflammatory phenotype during endotoxemia remains elusive. We previously identified Gdf3 , a TGFβ superfamily cytokine, as a top-regulated gene by age and the NLRP3 inflammasome in adipose tissue macrophages (ATMs). Here, we demonstrate that endotoxemia increases inflammatory (CD11c + ) ATMs in a Gdf3- dependent manner in old mice. Lifelong systemic or myeloid-specific deletion of Gdf3 leads to reduced endotoxemia- induced inflammation, with decreased CD11c + ATMs and inflammatory cytokines, and protection from hypothermia. Moreover, acute blockade of Gdf3 using JQ1, a BRD4 inhibitor, phenocopies old mice with lifelong Gdf3- deficiency. We show that GDF3 promotes the inflammatory phenotype in ATMs by phosphorylating SMAD2/3. Mechanistically, the differential chromatin landscape of ATMs from old mice with or without myeloid-driven Gdf3 indicates that GDF3- SMAD2/3 signaling axis shifts the chromatin accessibility of ATMs towards an inflammatory state during aging. Furthermore, pharmaceutical inhibition of SMAD3 with a specific inhibitor of SMAD3 (SIS3) mimics Gdf3 deletion. SIS3 reduces endotoxemia-mediated inflammation with fewer CD11c + ATMs and less severe hypothermia in old, but not young mice, as well as reduced mortality. In human adipose tissue, age positively correlates with GDF3 level, while inflammation correlates with pSMAD2/3 level. Overall, these results highlight the importance of GDF3-SMAD2/3 axis in driving inflammation in older organisms and identify this signaling axis as a promising therapeutic target for mitigating endotoxemia-related inflammation in the aged.

TGFβ is a pleiotropic signaling pathway that plays a pivotal role in regulating a multitude of cellular functions. TGFβ has a dual role in cell regulation where it induces growth inhibition and cell death; however, it can switch to a growth-promoting state under cancerous conditions. TGFβ is upregulated in colorectal cancer and pancreatic cancer, altering the tumor microenvironment and immune system and promoting a mesenchymal state. The upregulation of TGFβ in certain cancers leads to resistance to immunotherapy, and attempts to inhibit TGFβ expression have led to reduced therapeutic resistance when combined with chemotherapy and immunotherapy. Here, we review the current TGFβ inhibitor drugs in clinical trials for pancreatic and colorectal cancer, with the goal of uncovering advances in improving clinical efficacy for TGFβ combinational treatments in patients. Furthermore, we discuss the relevance of alterations in TGFβ signaling and germline variants in the context of personalizing treatment for patients who show lack of response to current therapeutics.

Transforming growth factor β (TGF-β) is a ubiquitous molecule that is extremely conserved structurally and plays a systemic role in human organism. TGF-β is a homodimeric molecule consisting of two subunits joined through a disulphide bond. In mammals, three genes code for TGF-β1, TGF-β2, and TGF-β3 isoforms of this cytokine with a dominating expression of TGF-β1. Virtually, all normal cells contain TGF-β and its specific receptors. Considering the exceptional role of fine balance played by the TGF-β in anumber of physiological and pathological processes in human body, this cytokine may be proposed for use in medicine as an immunosuppressant in transplantology, wound healing and bone repair. TGFb itself is an important target in oncology. Strategies for blocking members of TGF-β signaling pathway as therapeutic targets have been considered. In this review, signalling mechanisms of TGF-β1 action are addressed, and their role in physiology and pathology with main focus on carcinogenesis are described.

Brain arteriovenous malformations (bAVMs) substantially increase the risk for intracerebral hemorrhage (ICH), which is associated with significant morbidity and mortality. However, the treatment options for bAVMs are severely limited, primarily relying on invasive methods that carry their own risks for intraoperative hemorrhage or even death. Currently, there are no pharmaceutical agents shown to treat this condition, primarily due to a poor understanding of bAVM pathophysiology. For the last decade, bAVM research has made significant advances, including the identification of novel genetic mutations and relevant signaling in bAVM development. However, bAVM pathophysiology is still largely unclear. Further investigation is required to understand the detailed cellular and molecular mechanisms involved, which will enable the development of safer and more effective treatment options. Endothelial cells (ECs), the cells that line the vascular lumen, are integral to the pathogenesis of bAVMs. Understanding the fundamental role of ECs in pathological conditions is crucial to unraveling bAVM pathophysiology. This review focuses on the current knowledge of bAVM-relevant signaling pathways and dysfunctions in ECs, particularly the endothelial-to-mesenchymal transition (EndMT).

The role of estrogens in prostate cancer (PCa) is shrouded in mystery, with its actions going from angelic to devilish. The findings by Huggins and Hodges establishing PCa as a hormone-sensitive cancer have provided the basis for using estrogens in therapy. However, despite the clinical efficacy in suppressing tumor growth and the panoply of experimental evidence describing its anticarcinogenic effects, estrogens were abolished from PCa treatment because of the adverse secondary effects. Notwithstanding, research work over the years has continued investigating the effects of estrogens, reporting their pros and cons in prostate carcinogenesis. In contrast with the beneficial therapeutic effects, many reports have implicated estrogens in the disruption of prostate cell fate and tissue homeostasis. On the other hand, epidemiological data demonstrating the lower incidence of PCa in Eastern countries associated with a higher consumption of phytoestrogens support the beneficial role of estrogens in counteracting cancer development. Many studies have investigated the effects of phytoestrogens and the underlying mechanisms of action, which may contribute to developing safe estrogen-based anti-PCa therapies. This review compiles the existing data on the anti- and protumorigenic actions of estrogens and summarizes the anticancer effects of several phytoestrogens, highlighting their promising features in PCa treatment.

While many genes linked to colorectal cancer (CRC) contribute to cancer development, a thorough investigation is needed to explore crucial hub genes yet to be fully studied. A pivotal pathway in CRC is transforming growth factor-beta (TGF-β). This study aimed to assess SMAD2 and SMAD4 gene expression from this pathway.

Counted data from the Cancer Genome Atlas (TCGA) were examined, comparing 483 tumor and 41 normal samples. Using clinical data, genes impacting overall survival (OS) were evaluated. GSE39582 was employed to confirmed the levels of genes in CRC compared to the normal samples. Additionally, employing unhealthy samples and the RT-qPCR means our outcomes was validated. Finally, PharmacoGx information were utilized to connect the levels of potential genes to drug tolerance and susceptibility. Our findings showed SMAD2 and SMAD4 levels in TGF-β signaling were more significant than other pathway genes. Our findings indicated that the protein levels of these genes were lower in malignant tissues than in healthy tissues. Results revealed a significant correlation between low levels of SMAD2 and unfavorable OS in CRC individuals. RT-qPCR results demonstrated decreased expressions of both SMAD2 and SMAD4 in cancer tissues compared to elevated levels in adjacent normal samples. Our results showed significant association between selected genes and immune cell infiltration markers such as CD8+, and B-cells. Our results indicated a potential association among the levels of SMAD2 and SMAD4 genes and tolerance and susceptibility to Nilotinib and Panobinostat drugs.

Reduced expression of SMAD2 and SMAD4 may be pivotal in CRC progression, impacting downstream genes unrelated to patient OS. These findings suggest a potential role for SMAD2 and SMAD4 as predictive markers for drug response in CRC patients.

TGF-β1/Smads is a classic signaling pathway, which plays important roles in the development process of organisms. Black porgy Acanthopagrus schlegelii and red porgy Pagrus major are valuable economic fishes, and their hybrid offspring show excellent heterosis traits. Yet the molecular regulation mechanism of the heterosis traits is less clear. Here, we explored the TGF-β1/Smads pathway's molecular genetic information for heterosis in A. schlegelii ♂ × P. major ♀ (AP) and A. schlegelii ♀ × P. major ♂ (PA) in terms of growth and development. The mRNA expression levels of TGF-β1, TβR-I, TβR-II, and Smad2 genes in different developmental stages of A. schlegelii were detected. Furthermore, the expression levels of TGF-β1, TβR-I, TβR-II, and Smad2 genes in different tissues of adult (mRNA level) and larva (mRNA and protein level) of A. schlegelii, P. major, and their hybrids were determined by both real-time quantitative PCR and Western blot techniques. The results indicated the ubiquitous expression of these genes in all developmental stages of A. schlegelii and in all tested tissues of A. schlegelii, P. major, and its hybrids. Among them, the mRNA of TGF-β1, TβR-I, and TβR-II genes is highly expressed in the liver, gill, kidney, and muscle of black porgy, red porgy, and their hybrid offspring. There are significant changes in gene and protein expression levels in hybrid offspring, which indirectly reflect hybrid advantage. In addition, there was no correlation between protein and mRNA expression levels of Smad2 protein. The results provide novel data for the differential expression of growth and development genes between the reciprocal hybridization generation of black porgy and red porgy and its parents, which is conducive to further explaining the molecular regulation mechanism of heterosis in the growth and development of hybrid porgy.

Corticotroph pituitary neuroendocrine tumors (PitNETs), associated with Cushing's disease (CD), have limited treatment options other than surgical resection. Bone morphogenetic protein 4 (BMP4), a potential therapeutic target, is decreased in patients with CD. Previous studies have identified BMPSB4 as a potent agonist of the BMP4 signaling pathway. Here, we investigated the effect of BMPSB4 on the corticotroph PitNET cell line AtT20/D16v-F2 and explored the underlying mechanisms and therapeutic potential. We verified the low expression patterns of BMP4 and downstream p-SMAD1/5/9 in CD samples at the transcriptional and protein levels. In addition, BMPSB4 activated SMAD1/5/9 in a time- and concentration-dependent manner, with concomitant inhibitory effects on AtT20/D16v-F2 cells. Further RNA sequencing, transmission electron microscopy (TEM), and transfection with the mRFP-EGFP-LC3 adenoviral vector revealed that BMPSB4 induced cellular autophagy, which was the basis for the inhibitory effect of BMPSB4. Moreover, we demonstrated that autophagy induced by BMPSB4 was achieved through the SMADs-dependent pathway. In vivo, BMPSB4 inhibited tumor growth and significantly reduced adrenocorticotrophin (ACTH) and corticosterone (CORT) secretion, thereby alleviating the CD phenotype. In conclusion, this study identified BMPSB4 as an effective therapeutic agent for CD. BMPSB4 activates autophagy through a SMADs-dependent pathway, which in turn promotes autophagy-mediated cell death. Our work further elucidates the mechanism of the BMP4 signaling pathway in CD and suggests broad prospects for the development and application of BMPSB4 in CD therapy.

The placenta is a unique and pivotal organ in reproduction, controlling crucial growth and cell differentiation processes that ensure a successful pregnancy. Placental development is a tightly regulated and dynamic process, in which the transforming growth factor beta (TGFβ) superfamily plays a central role. This family of pleiotropic growth factors is heavily involved in regulating various aspects of reproductive biology, particularly in trophoblast differentiation during the first trimester of pregnancy. TGFβ signalling precisely regulates trophoblast invasion and the cell transition from cytotrophoblasts to extravillous trophoblasts, which is an epithelial-to-mesenchymal transition-like process. Later in pregnancy, TGFβ signalling ensures proper vascularization and angiogenesis in placental endothelial cells. Beyond its role in trophoblasts and endothelial cells, TGFβ signalling contributes to the polarization and function of placental and decidual macrophages by promoting maternal tolerance of the semi-allogeneic foetus. Disturbances in early placental development have been associated with several pregnancy complications, including preeclampsia (PE) which is one of the severe complications. Emerging evidence suggests that TGFβ is involved in the pathogenesis of PE, thereby offering a potential target for intervention in the human placenta.

This comprehensive review aims to explore and elucidate the roles of the major members of the TGFβ superfamily, including TGFβs, bone morphogenetic proteins (BMPs), activins, inhibins, nodals, and growth differentiation factors (GDFs), in the context of placental development and function. The review focusses on their interactions within the major cell types of the placenta, namely trophoblasts, endothelial cells, and immune cells, in both normal pregnancies and pregnancies complicated by PE throughout pregnancy.

A literature search was carried out using PubMed and Google Scholar, searching terms: 'TGF signalling preeclampsia', 'pregnancy TGF signalling', 'preeclampsia tgfβ', 'preeclampsia bmp', 'preeclampsia gdf', 'preeclampsia activin', 'endoglin preeclampsia', 'endoglin pregnancy', 'tgfβ signalling pregnancy', 'bmp signalling pregnancy', 'gdf signalling pregnancy', 'activin signalling pregnancy', 'Hofbauer cell tgfβ signalling', 'placental macrophages tgfβ', 'endothelial cells tgfβ', 'endothelium tgfβ signalling', 'trophoblast invasion tgfβ signalling', 'trophoblast invasion Smad', 'trophoblast invasion bmp', 'trophoblast invasion tgfβ', 'tgfβ preeclampsia', 'tgfβ placental development', 'TGFβ placental function', 'endothelial dysfunction preeclampsia tgfβ signalling', 'vascular remodelling placenta TGFβ', 'inflammation pregnancy tgfβ', 'immune response pregnancy tgfβ', 'immune tolerance pregnancy tgfβ', 'TGFβ pregnancy NK cells', 'bmp pregnancy NK cells', 'bmp pregnancy tregs', 'tgfβ pregnancy tregs', 'TGFβ placenta NK cells', 'TGFβ placenta tregs', 'NK cells preeclampsia', 'Tregs preeclampsia'. Only articles published in English until 2023 were used.

A comprehensive understanding of TGFβ signalling and its role in regulating interconnected cell functions of the main placental cell types provides valuable insights into the processes essential for successful placental development and growth of the foetus during pregnancy. By orchestrating trophoblast invasion, vascularization, immune tolerance, and tissue remodelling, TGFβ ligands contribute to the proper functioning of a healthy maternal-foetal interface. However, dysregulation of TGFβ signalling has been implicated in the pathogenesis of PE, where the shallow trophoblast invasion, defective vascular remodelling, decreased uteroplacental perfusion, and endothelial cell and immune dysfunction observed in PE, are all affected by an altered TGFβ signalling.

The dysregulation of TGFβ signalling in PE has important implications for research and clinical practice. Further investigation is required to understand the underlying mechanisms, including the role of different ligands and their regulation under pathophysiological conditions, in order to discover new therapeutic targets. Distinguishing between clinically manifested subtypes of PE and studying TGFβ signalling in different placental cell types holistically is an important first step. To put this knowledge into practice, pre-clinical animal models combined with new technologies are needed. This may also lead to improved human research models and identify potential therapeutic targets, ultimately improving outcomes for affected pregnancies and reducing the burden of PE.

Intracellular signaling by the pleiotropic cytokine transforming growth factor-β (TGF-β) is inhibited by Smad7 in a feedback control mechanism. The activity of Smad7 is tightly regulated by multiple post-translational modifications. Using resin-assisted capture and metabolic labeling methods, we show here that Smad7 is S-palmitoylated in mammary epithelial cell models that are widely studied because of their strong responses to TGF-β and their biological relevance to mammary development and tumor progression. S-palmitoylation of Smad7 is mediated by zDHHC17, a member of a family of 23 S-acyltransferase enzymes. Moreover, we identified four cysteine residues (Cys202, Cys225, Cys415, and Cys417) in Smad7 as palmitoylation acceptor sites. S-palmitoylation of Smad7 on Cys415 and Cys417 promoted the translocation of Smad7 from the nucleus to the cytoplasm, enhanced the stability of the Smad7 protein, and enforced its inhibitory effect on TGF-β-induced Smad transcriptional response. Thus, our findings reveal a new post-translational modification of Smad7, and highlight an important role of S-palmitoylation to enhance inhibition of TGF-β/Smad signaling by Smad7.

Maternal malnutrition can alter developmental biology, programming health and disease in offspring. The increase in sugar consumption during the peripubertal period, a worldwide concern, also affects health through adulthood. Studies have shown that maternal exposure to a low protein diet (LPD) is associated with an increase in prostate disease with aging. However, the combined effects of maternal LPD and early postnatal sugar consumption on offspring prostate disorders were not investigated. The effects on aging were evaluated using a maternal gestational model with lactational LPD (6% protein) and sugar consumption (10%) from postnatal day (PND) 21-90, associating the consequences on ventral prostate (VP) rats morphophysiology on PND540. An increase was shown in mast cells and in the VP of the CTR + SUG and Gestational and Lactational Low Protein (GLLP) groups. In GLLP + SUG, a significant increase was shown in TGF-β1 expression in both the systemic and intra-prostatic forms, and SMAD2/3p had increased. The study identified maternal LPD and sugar consumption as risk factors for prostatic homeostasis in senility, activating the TGFβ1-SMAD2/3 pathway, a signaling pathway with potential markers for prostatic disorders.