Growth Factor Beta Signaling Pathway Research Articles

JOSD2 promotes breast cancer metastasis by deubiquitinating and stabilizing SMAD4.

Breast cancer is one of the most common malignant tumors among women worldwide, and its high degree of metastasis significantly impacts treatment effectiveness leading to poor prognosis. The potential molecular mechanisms underlying breast cancer metastasis remain to be further elucidated. In this study, via database analysis, we revealed that the deubiquitinase josephin domain containing 2 (JOSD2) was abnormally amplified in patients with metastatic breast cancer, and was significantly negatively correlated with patient prognosis. By integrating data from the Gene Expression Omnibus (GEO) database and Kyoto Encyclopedia of Genes and Genomes (KEGG) signaling pathway enrichment analysis, we found that the transforming growth factor beta (TGF-β) signaling pathway was significantly activated in breast cancer patients with increased JOSD2 expression. Further studies revealed that JOSD2 interacted with and stabilized SMAD family member 4 (SMAD4) by removing polyubiquitin chains. Inhibition of JOSD2 by RNA interference effectively inhibited the metastasis of breast cancer cells both in vitro and in vivo. In conclusion, our study not only reveals the role of JOSD2 in promoting breast cancer metastasis for the first time, but also indicates promising directions for the future development of deubiquitinase inhibitors, which could yield significant therapeutic benefits. Nevertheless extensive research and development are required to fully realize this potential.

Marfan syndrome: insights from animal models.

Marfan syndrome (MFS) is an inherited disorder that affects the connective tissues and mainly presents in the bones, eyes, and cardiovascular system, etc. Aortic pathology is the leading cause of death in patients with Marfan syndrome. The fibrillin-1 gene (FBN1) is a major gene involved in the pathogenesis of MFS. It has been shown that the aortic pathogenesis of MFS is associated with the imbalances of the transforming growth factor-beta (TGF-β) signaling pathway. However, the exact molecular mechanism of MFS is unclear. Animal models may partially mimic MFS and are vital to the study of MFS. Several species of animals have been used for MFS studies, including chicks, cattle, mice, pigs, zebrafishes, Caenorhabditis elegans, and rabbits. These models were developed spontaneously or in combination with genetic engineering techniques. This review is to describe the TGF-β signaling pathway in MFS and the potential application of animal models to provide new therapeutic strategies for patients with MFS.

Protogenin facilitates trunk-to-tail HOX code transition via modulating GDF11/SMAD2 signaling in mammalian embryos

During embryogenesis, vertebral axial patterning is intricately regulated by multiple signaling networks. This study elucidates the role of protogenin (Prtg), an immunoglobulin superfamily member, in vertebral patterning control. Prtg knockout (Prtg−/−) mice manifest anterior homeotic transformations in their vertebral columns and significant alterations in homeobox (Hox) gene expression. Transcriptomic profiling of Prtg−/− mouse embryos highlights Prtg-regulated genes involved in axial development, particularly within the transforming growth factor beta (TGFβ) signaling pathway. Reduced TGFβ signaling in Prtg−/− mouse embryos is evidenced by decreased phosphorylated Smad2 (pSmad2) levels and its downstream target genes in the developing tail. We further show that Prtg interacts with growth differentiation factor 11 (GDF11) to enhance GDF11/pSmad2 signaling activity. Using human-induced pluripotent stem cell-derived presomitic mesoderm-like (hiPSC-PSM) cells, we demonstrate delayed posterior HOX gene expression upon PRTG knockout, which is rescued by GDF11 supplementation. These findings provide compelling evidence that PRTG regulates HOX genes through the GDF11/SMAD2 signaling pathway.

Therapeutic potential of SMAD7 targeting miRNA in the pathogenesis of diabetic nephropathy.

Diabetic nephropathy (DN) is a common complication of diabetes and a leading cause of end-stage renal disease, characterized by progressive kidney fibrosis and inflammation. The transforming growth factor-beta (TGF-β) signaling pathway plays a crucial role in the pathogenesis of diabetes nephropathy, and SMAD7 is a key negative regulator of this pathway. Recent studies have highlighted the involvement of miRNA in the progression of DN. Computational analysis identified 11 potential miRNAs such as miR-424, miR-195, miR-216a, miR-503, miR-15a-5p, miR-15b-5p, miR-665, miR-520h, miR16-5p, miR-21 and miR-32-5p which are predicted to target 3'UTR of SMAD7 mRNA. This review aims to explore the role of these miRNAs in the progression of DN. Notably, these miRNAs have shown therapeutic potential in mitigating fibrosis and inflammation by modulating SMAD7 expression in DN. Future directions can be to investigate the mechanistic pathways through which these miRNAs exert their effects, as well as optimizing delivery systems for effective clinical application. Targeting miRNAs that modulate SMAD7 expression represents a promising strategy for developing specific and effective therapies for diabetic nephropathy.

Chromatin remodelling in damaged intestinal crypts orchestrates redundant TGFβ and Hippo signalling to drive regeneration.

Cell state dynamics underlying successful tissue regeneration are undercharacterized. In the intestine, damage prompts epithelial reprogramming into revival stem cells (revSCs) that reconstitute Lgr5+ intestinal stem cells (ISCs). Here single-nuclear multi-omics of mouse crypts regenerating from irradiation shows revSC chromatin accessibility overlaps with ISCs and differentiated lineages. While revSC genes themselves are accessible throughout homeostatic epithelia, damage-induced remodelling of chromatin in the crypt converges on Hippo and the transforming growth factor-beta (TGFβ) signalling pathway, which we show is transiently activated and directly induces functional revSCs. Combinatorial gene expression analysis further suggests multiple sources of revSCs, and we demonstrate TGFβ can reprogramme enterocytes, goblet and paneth cells into revSCs and show individual revSCs form organoids. Despite this, loss of TGFβ signalling yields mild regenerative defects, whereas interference in both Hippo and TGFβ leads to profound defects and death. Intestinal regeneration is thus poised for activation by a compensatory system of crypt-localized, transient morphogen cues that support epithelial reprogramming and robust intestinal repair.

Possible involvement of Jun, Foxo1, Nobox in the regulation of smad2/3 transcription in the protogynous hermaphroditic ricefield eel (Monopterus albus)

Small mothers against decapentaplegic2/3 (Smad2/3) are two signalling intermediates in the transforming growth factor beta (TGF-β) signalling pathway, which plays a critical role in gonad development. However, a systemic analysis of Smad2/3 in Monopterus albus (M. albus) has not been performed. The smad2 sequence in M. albus was characterized in our previous publication. In this study, we characterized the nucleotide sequence of smad3 and reported that smad3 is widely expressed in different tissues of M. albus. Importantly, the expression of smad3 significantly increased at the early vitellogenic stage in the ovary and decreased with oocyte maturation. Next, we aimed to identify the upstream factors that regulate Smad2/3 transcription. The 5′ flanking sequences of smad2/3 were cloned, and their core promoter regions were determined to be between −447 bp and −100 bp and between −1520 bp and −927 bp, respectively. The Jun and Foxo1 binding sites were conserved in the smad2 promoter region, and the Sp1, Bcl-6, and Nobox binding sites were conserved in the smad3 promoter region. Through dual-luciferase reporter gene experiments, we showed that Jun and Foxo1 binding sites may be involved in the regulation of smad2 transcription, whereas the Nobox binding site may be involved in the activation of the smad3 promoter.

Comprehensive mapping of somatotroph pituitary neuroendocrine tumour heterogeneity using spatial and single-cell transcriptomics.

Pituitary neuroendocrine tumours (PitNETs) are common intracranial tumours that are highly heterogeneous with unpredictable growth patterns. The driver genes and mechanisms that are crucial for tumour progression in somatotroph PitNETs are poorly understood. In this study, we performed integrative spatial transcriptomics (ST) and single-cell RNA sequencing (scRNA-seq) analysis on somatotroph tumours and normal pituitary samples to comprehensively characterize the differences in cellular characteristics. By analyzing combined copy number variations (CNVs), tumour tissues were divided into two regions, which included the CNVhigh and CNVlow areas. The protumour genes DLK1 and RCN1 were highly expressed in the CNVhigh area, which might be related to tumour progression and could be targeted for precision therapy. We also found that the transforming growth factor beta signalling pathway participated in tumour progression and identified heterogeneity in the expression profiles of key genes. We assessed the intertumoral and intratumoral heterogeneity in somatotroph PitNETs and emphasized the importance of individualized treatment. In summary, we visualized the cellular distribution and transcriptional differences in normal pituitary and somatotroph PitNETs by ST and scRNA-seq for the first time. This study provides a strong theoretical foundation to comprehensively understand the crucial mechanisms involved in tumour progression and develop new strategies to treat somatotroph PitNETs. The first-ever visualization of cellular distributions in normal and tumor pituitary tissues. The inter- and intra-tumoral transcriptomic heterogeneity of somatotroph PitNETs was comprehensively revealed. Identification of potential protumor factors and critical signaling pathways, opening new avenues for therapeutic intervention.

Traditional Chinese Herbal Medicine: Therapeutic Potential in Chronic Obstructive Pulmonary Disease

Chronic obstructive pulmonary disease (COPD) is characterized by persistent airflow obstruction and manifested by symptoms such as chronic cough, sputum, and dyspnea. Traditional Chinese medicine (TCM) has long been used to treat COPD. This article summarizes potential Chinese herbal medicines (CHM) for COPD treatment through a literature review and collation. The findings highlight 14 kinds of effective CHM for COPD, including Scutellaria radix, Salvia miltiorrhiza radix et rhizoma, Hippophae fructus, Ginseng radix et rhizoma, and Astragali radix. Flavonoids, terpenoids, alkaloids, and volatile oil constituents are the main bioactive components for the treatment of COPD. They mainly inhibit the tumor necrosis factor alpha/nuclear factor kappa B (TNF-α/NF-κB) signaling pathway by reducing the production and release of inflammatory factors such as interleukin 1 beta (IL-1β), interleukin 6 (IL-6), interleukin 8 (IL-8), TNF-α, and NF-κB, thereby reducing inflammation in lungs of rats with COPD and protect the lung tissues. Some active ingredients can inhibit toll-like receptor 4 (TLR4), mitogen-activated protein kinase (MAPK), phosphoinositide 3-kinase-protein kinase B (PI3K-Akt), Janus kinase-signal transducer and activator of transcription (JAK-STAT), and transforming growth factor beta (TGF-β) signaling pathways to express anti-inflammatory activity. This work establishes a foundation for using CHM in COPD treatment and offers new insights and approaches for developing novel anti-COPD drugs.

Assessing TGF-β Prognostic Model Predictions for Chemotherapy Response and Oncogenic Role of FKBP1A in Liver Cancer.

The Transforming Growth Factor-Beta (TGF-β) signaling pathway plays a crucial role in the pathogenesis of diseases. This study aimed to identify differentially expressed TGF-β-related genes in liver cancer patients and to correlate these findings with clinical features and immune signatures. The TCGA-STAD and LIRI-JP cohorts were utilized for a comprehensive analysis of TGF-β- related genes. Differential gene expression, functional enrichment, survival analysis, and machine learning techniques were employed to develop a prognostic model based on a TGF-β-related gene signature (TGFBRS). We developed a prognostic model for liver cancer based on the expression levels of nine TGF-β- related genes. The model indicates that higher TGFBRS values are associated with poorer prognosis, higher tumor grades, more advanced pathological stages, and resistance to chemotherapy. Additionally, the TGFBRS-High subtype was characterized by elevated levels of immune-suppressive cells and increased expression of immune checkpoint molecules. Using a Gradient Boosting Decision Tree (GBDT) machine learning approach, the FKBP1A gene was identified as playing a significant role in liver cancer. Notably, knocking down FKBP1A significantly inhibited the proliferation and metastatic capabilities of liver cancer cells both in vitro and in vivo. Our study highlights the potential of TGFBRS in predicting chemotherapy responses and in shaping the tumor immune microenvironment in liver cancer. The results identify FKBP1A as a promising molecular target for developing preventive and therapeutic strategies against liver cancer. Our findings could potentially guide personalized treatment strategies to improve the prognosis of liver cancer patients.

Single-cell RNA sequencing analysis reveals the role of TXNDC5 in keloid formation.

Thioredoxin domain-containing protein 5 (TXNDC5) is associated with fibrosis in a variety of organs, but its mechanism of action in keloid is unclear. In this study, we aimed to investigate the mechanism of TXNDC5 in keloid. Single-cell RNA sequencing data of keloid and normal scar samples obtained from public databases were normalized and clustered using the Seurat package. Pathway enrich analysis was conducted using biological process enrichment analysis and Gene Set Enrichment Analysis (GSEA). In addition, TXNDC5 expression and its effects on migration and invasion of keloid fibroblasts (KFs) were validated based on cell function experiments. A total of five cell types were obtained. The KF clusters were further clustered into two fibroblast subtypes (Fibroblast cells 1 and Fibroblast cells 2). Biological process enrichment analysis showed that transforming growth factor beta (TGF-β) signaling pathway was enriched in the two fibroblast subtypes. GSEA analysis demonstrated that genes in TGF-β signaling pathway were mainly enriched in Fibroblast cells 1, and that genes involved in cell proliferation, migration, and the TGF-β signaling pathway were all high-expressed in fibroblast cells 1. TXNDC5 was positively correlated with fibroblast proliferation, migration and TGF-β signaling pathway, and AUCell score. The cellular experiment confirmed that the messenger RNA and protein levels of TXNDC5 and TGF-β1 were high-expressed in KFs cells (P<0.001), and that knockdown of TXNDC5 downregulated TGF-β1 expression and inhibited migration and invasion of KFs (P<0.0001). Our study indicated that TGF-β signaling pathway was enriched in fibroblast cells, and TXNDC5 was positively correlated with proliferation, migration, and TGF-β signaling pathway. Cellular experiment demonstrated that knocking down TXNDC5 downregulated TGF-β1 expression, and suppressed migration and invasion of KFs. The current discoveries provided a new therapeutic strategy for the treatment of keloid.

Potential effects of a human milk oligosaccharide 6'-sialyllactose on angiotensin II-induced aortic aneurysm via p90RSK/TGF-β/SMAD2 signaling pathway.

The aberrant phenotypic transformation of vascular smooth muscle cells (VSMCs) is a key factor in the formation of aortic aneurysm (AA). This study aimed to explore theeffects of 6'-sialyllactose (6'-SL), a human milk oligosaccharide, on angiotensin II (Ang II)-induced VSMC dysfunction and AA formation both in vitro and in vivo. An AA model was established in male C57BL/6 mice challenged with Ang II via osmotic pumps and a lysyl oxidase inhibitor, β-aminopropionitrile (BAPN), in drinking water. The mice were administered with 6'-SL, FMK (a p90RSK inhibitor), or losartan (as a positive control). In vitro, VSMCs were pretreated with 6'-SL before Ang II stimulation. We found that p90RSK inhibition abolished Ang II/BAPN-induced thoracic AA and abdominal AA formation. Treatment with 100mg/kg 6'-SL significantly attenuated Ang II/BAPN-induced aortic dilatation. 6'-SL attenuated Ang II-induced collagen deposition, calcification, and immune cell accumulation. Consistently, 6'-SL downregulated p-p90RSK, p90RSK, and p-SMAD2, and mitigated VSMC contractility loss, as indicated by α-SMA expression in vivo. Interestingly, Ang II-induced transforming growth factor-beta (TGF-β) signaling pathway was suppressed by p90RSK inhibition in VSMCs. 6'-SL treatment significantly reduced TGF-β/SMAD2 targets, including dedifferentiation markers such asosteopontin and vimentin, and elastin degradation factors MMP2 and MMP9. Overexpression of p90RSK in VSMCs enhanced TGF-β and abrogated the effects of 6'-SL. Furthermore, 6'-SL co-treatment abolished high phosphate-induced calcification in vitro via p90RSK/TGF-β signaling pathway. Altogether, our findings suggest that 6'-SL could be a potential therapeutic candidate for protecting against Ang II-induced AA formation by inhibiting the p90RSK/TGF-β/SMAD2 signaling pathway.

MiRNAs in umbilical Wharton’s jelly in neonates with different birth weights: A pilot study

BackgroundBirth weight is a critical indicator of perinatal health. miRNAs are small non-coding RNA molecules, ranging from 18 to 25 nucleotides in length, that regulate gene expression. Specific miRNAs have been implicated in metabolic pathways influencing fetal growth, and their dysregulation may contribute to variations in birth weight. Our objective was to isolate amplifiable miRNAs from umbilical cord tissue and compare their expression across three patient groups. MethodsThe study sample comprised 23 patients: 8 small for gestational age (SGA), 10 large for gestational age (LGA), and 5 appropriate for gestational age (AGA). Umbilical cord tissue samples were collected immediately after childbirth, stored, and subsequently processed. The miRNA expression profile of these samples was analyzed using high-throughput sequencing, and the results were evaluated through bioinformatic analysis. ResultsWe identified significant differences in the expression levels of 6 miRNAs. miR-324-3p was downregulated in SGA compared to both AGA and LGA groups. Conversely, miR-337-3p was upregulated in LGA compared to both SGA and AGA. miR-760 was downregulated in LGA relative to SGA and AGA, while miR-4707-3p, miR-548a-3p, and miR-6733-5p were upregulated in both SGA and LGA compared to AGA. Most of these miRNAs appear to be associated with the transforming growth factor-beta signaling pathway. ConclusionsThis exploratory study suggests that miRNA expression in umbilical cord tissue is associated with birth weight. Notably, the downregulation of miR-324-3p in SGA newborns indicates that its decreased expression may be related to SGA conditions.

Overexpression of ATF4 Inhibits Ferroptosis to Alleviate Anxiety Disorders by Activating the TGF-β Signaling Pathway.

Anxiety disorders seriously impair patients' mental health and quality of life, with limited effectiveness of current treatments. Dysregulation of activating transcription factor 4 (ATF4) is involved in various mental diseases, but the research on its potential roles in alleviating anxiety disorders remains limited. ATF4 was screened out by bioinformatic analysis and its expression was verified in vivo. Mice were treated with 21 d of chronic restraint stress to establish the anxiety mice model. The anxiolytic effect of ATF4 was assessed by a battery of behavior tests and evaluation of hippocampal tissue damage after overexpressing ATF4. Ferroptosis-related indicators were detected by enzyme-linked immunosorbent assay and Western blotting. Then the transforming growth factor beta (TGF-β) signaling pathway was predicted as the downstream regulatory pathway of ATF4 by bioinformatic methods. Western blotting was conducted to detect the protein expression level of TGF-β1, small mothers against decapentaplegic 3 (Smad3), and phospho-Smad3 (p-Smad3). ATF4 was screened out as a ferroptosis-related anxiolytic gene after bioinformatics analysis and was down-regulated in the anxiety mice model. Mice with ATF4 overexpression spent more time in the open arms in the elevated plus-maze test, appeared more frequently in the central area in the open-field test, and decreased the immobility time in the forced swimming and tail suspension tests. Hippocampal tissue damage was alleviated, ferroptosis was suppressed, and the levels of TGF-β1 and p-Smad3/Smad3 were increased by AFT4 overexpression. ATF4 overexpression can repress ferroptosis to improve anxiety disorders by activating the TGF-β signaling pathway.

CircSMAD3 represses VSMC phenotype switching and neointima formation via promoting hnRNPA1 ubiquitination degradation.

Circular RNAs (circRNAs) are novel regulatory RNAs with high evolutionary conservation and stability, which makes them effective therapeutic agents for various vascular diseases. The SMAD family is a downstream mediator of the canonical transforming growth factor beta (TGF-β) signalling pathway and has been considered as a critical regulator in vascular injury. However, the role of circRNAs derived from the SMAD family members in vascular physiology remains unclear. In this study, we initially identified potential functional circRNAs originating from the SMAD family using integrated transcriptome screening. circSMAD3, derived from the SMAD3 gene, was identified to be significantly downregulated in vascular injury and atherosclerosis. Transcriptome analysis was conducted to comprehensively illustrate the pathways modulated by circRNAs. Functionally, circSMAD3 repressed vascular smooth muscle cell (VSMC) proliferation and phenotype switching in vitro evidenced by morphological assays, and ameliorated arterial injury-induced neointima formation in vivo. Mechanistically, circSMAD3 interacted with heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1) within the nucleus, enhanced its interaction with E3 ligase WD repeat domain 76 to promote hnRNPA1 ubiquitination degradation, facilitated p53 pre-RNA splicing, activated the p53γ signalling pathway, and finally suppressed VSMC proliferation and phenotype switching. Our study identifies circSMAD3 as a novel epigenetic regulator that suppresses VSMC proliferation and phenotype switching, thereby attenuating vascular remodelling and providing a new circRNA-based therapeutic strategy for cardiovascular diseases.

The TGFβ type I receptor kinase inhibitor vactosertib in combination with pomalidomide in relapsed/refractory multiple myeloma: a phase 1b trial

Functional blockade of the transforming growth factor-beta (TGFβ) signalling pathway improves the efficacy of cytotoxic and immunotherapies. Here, we conducted a phase 1b study (ClinicalTrials.gov., NCT03143985) to determine the primary endpoints of safety, tolerability, and maximal tolerated dose (200 mg twice daily) for the orally-available TGFβ type I receptor kinase inhibitor vactosertib in combination with pomalidomide in relapsed and/or refractory multiple myeloma (RRMM) patients who had received ≥2 lines of chemoimmunotherapy. Secondary endpoints demonstrated sustained clinical responses, favorable pharmacokinetic parameters and a 6-month progression-free survival of 82%. Vactosertib combined with pomalidomide was well-tolerated at all dose levels and displayed a manageable adverse event profile. Exploratory analysis indicated that vactosertib co-treatment with pomalidomide also reduced TGFβ levels in patient bone marrow as well as the level of CD8+ T-cells that expressed the immunoinhibitory marker PD-1. In vitro experiments indicated that vactosertib+pomalidomide co-treatment decreased the viability of MM cell lines and patient tumor cells, and increased CD8+ T-cell cytotoxic activity. Vactosertib is a safe therapeutic that demonstrates tumor-intrinsic activity and can overcome immunosuppressive challenges within the tumor microenvironment to reinvigorate T-cell fitness. Vactosertib offers promise to improve immunotherapeutic responses in heavily-pretreated MM patients refractory to conventional agents.

The Regulation of MicroRNA-21 by Interleukin-6 and Its Role in the Development of Fibrosis in Endometriotic Lesions.

Endometriosis is one of the most common causes of chronic pelvic pain and infertility that affects 10% of women of reproductive age. It is currently defined as the presence of endometrial epithelial and stromal cells at ectopic sites; however, advances in endometriosis research have some authors believing that endometriosis should be re-defined as "a fibrotic condition in which endometrial stroma and epithelium can be identified". microRNAs (miRNAs) are regulatory molecules that potentially play a role in endometriotic lesion development. There is evidence that suggests that miRNAs, including microRNA-21 (miR-21), participate in fibrotic processes in different organs, including the heart, kidney, liver and lungs. The objective of this study was to understand the role of miR-21 and the mechanisms that can contribute to the development of fibrosis by determining how IL-6 regulates miR-21 expression and how this miRNA regulates the transforming growth factor beta (TGF-β) signaling pathway to promote fibrosis. We investigated the expression of miR-21 in the baboon and mouse model of endometriosis and its correlation with fibrosis. We demonstrated that inflammation and fibrosis are present at a very early stage of endometriosis and that the inflammatory environment in the peritoneal cavity, which includes interleukin 6 (IL-6), can regulate the expression of miR-21 in vitro and in vivo.

Effect of Different Dietary Iron Contents on Liver Transcriptome Characteristics in Wujin Pigs.

Iron is an important trace element that affects the growth and development of animals and regulates oxygen transport, hematopoiesis, and hypoxia adaptations. Wujin pig has unique hypoxic adaptability and iron homeostasis; however, the specific regulatory mechanisms have rarely been reported. This study randomly divided 18 healthy Wujin piglets into three groups: the control group, supplemented with 100 mg/kg iron (as iron glycinate); the low-iron group, no iron supplementation; and the high-iron group, supplemented with 200 mg/kg iron (as iron glycinate). The pre-feeding period was 5 days, and the formal period was 30 days. Serum was collected from empty stomachs before slaughter and at slaughter to detect changes in the serum iron metabolism parameters. Gene expression in the liver was analyzed via transcriptome analysis to determine the effects of low- and high-iron diets on transcriptome levels. Correlation analysis was performed for apparent serum parameters, and transcriptome sequencing was performed using weighted gene co-expression network analysis to reveal the key pathways underlying hypoxia regulation and iron metabolism. The main results are as follows. (1) Except for the hypoxia-inducible factor 1 (HIF-1) content (between the low- and high-iron groups), significant differences were not observed among the serum iron metabolic parameters. The serum HIF-1 content of the low-iron group was significantly higher than that of the high-iron group (p < 0.05). (2) Sequencing analysis of the liver transcriptome revealed 155 differentially expressed genes (DEGs) between the low-iron and control groups, 229 DEGs between the high-iron and control groups, and 279 DEGs between the low- and high-iron groups. Bioinformatics analysis showed that the HIF-1 and transforming growth factor-beta (TGF-β) signaling pathways were the key pathways for hypoxia regulation and iron metabolism. Four genes were selected for qPCR validation, and the results were consistent with the transcriptome sequencing data. In summary, the serum iron metabolism parameter results showed that under the influence of low- and high-iron diets, Wujin piglets maintain a steady state of physiological and biochemical indices via complex metabolic regulation of the body, which reflects their stress resistance and adaptability. The transcriptome results revealed the effects of low-iron and high-iron diets on the gene expression level in the liver and showed that the HIF-1 and TGF-β signaling pathways were key for regulating hypoxia adaptability and iron metabolism homeostasis under low-iron and high-iron diets. Moreover, HIF-1α and HEPC were the key genes. The findings provide a theoretical foundation for exploring the regulatory pathways and characteristics of iron metabolism in Wujin pigs.

Protective effects of curcumin against spinal cord injury.

In parallel with population aging, the prevalence of neurological and neurodegenerative diseases has been dramatically increasing over the past few decades. Neurodegenerative diseases reduce the quality of life of patients and impose a high cost on the health system. These slowly progressive diseases can cause functional, perceptual, and behavioral deficits in patients. Therefore, neurodegenerative impairments have always been an interesting subject for scientists and clinicians. One of these diseases is spinal cord injury (SCI). SCI can lead to irreversible damage and is classified into two main subtypes: traumatic and non-traumatic, each with very different pathophysiological features. This review aims to gather relevant information about the beneficial effects of curcumin (Cur), with specific emphasis on its anti-inflammatory properties towards spinal cord injury (SCI) patients. The review collates data from extensive in-vitro, in-vivo, and clinical trials documenting the effects of CUR on SCI. It examines the modulation of pathophysiological pathways and regulation of the inflammatory cascades after CUR administration. Various pathophysiological processes involving the nuclear factor erythroid 2-related factor 2 (Nrf2), nuclear factor kappa B (NF-kB), and transforming growth factor beta (TGF-β) signaling pathways have been suggested to exacerbate damages resulting from SCI. CUR administration showed to modulate these signaling pathways which lead to attenuation of SCI complications. Anti-inflammatory compounds, particularly CUR, can modulate these pathophysiological pathways and regulate the inflammatory cascades. CUR, a well-known natural product with significant anti-inflammatory effects, has been extensively documented in experimental and clinical trials. Curcumin's potential to alter key steps in the Nrf2, NF-kB, and TGF-β signaling pathways suggests that it may play a role in attenuating SCI complications.

Understanding the Foreign Body Response via Single-Cell Meta-Analysis.

Foreign body response (FBR) is a universal reaction to implanted biomaterial that can affect the function and longevity of the implant. A few studies have attempted to identify targets for treating FBR through the use of single-cell RNA sequencing (scRNA-seq), though the generalizability of these findings from an individual study may be limited. In our study, we perform a meta-analysis of scRNA-seq data from all available FBR mouse studies and integrate these data to identify gene signatures specific to FBR across different models and anatomic locations. We identify subclusters of fibroblasts and macrophages that emerge in response to foreign bodies and characterize their signaling pathways, gene ontology terms, and downstream mediators. The fibroblast subpopulations enriched in the setting of FBR demonstrated significant signaling interactions in the transforming growth factor-beta (TGF-β) signaling pathway, with known pro-fibrotic mediators identified as top expressed genes in these FBR-derived fibroblasts. In contrast, FBR-enriched macrophage subclusters highly expressed pro-fibrotic and pro-inflammatory mediators downstream of tumor necrosis factor (TNF) signaling. Cell-cell interactions were additionally interrogated using CellChat, with identification of key signaling interactions enriched between fibroblasts and macrophages in FBR. By combining multiple FBR datasets, our meta-analysis study identifies common cell-specific gene signatures enriched in foreign body reactions, providing potential therapeutic targets for patients requiring medical implants across a myriad of devices and indications.

KLF10: a point of convergence in cancer cachexia.

Cancer-associated cachexia is a wasting syndrome entailing loss in body mass and a shortened life expectancy. There is currently no effective treatment to abrogate this syndrome, which leads to 20-30% of deaths in patients with cancer. While there have been advancements in defining signaling factors/pathways in cancer-induced muscle wasting, targeting the same in the clinic has not been as successful. Krüppel-like factor 10 (KLF10), a transcription factor implicated in muscle regulation, is regulated by the transforming growth factor-beta signaling pathway. This review proposes KLF10 as a potential convergence point of diverse signaling pathways involved in muscle wasting. KLF10 was discovered as a target of transforming growth factor-beta decades ago but more recently it has been shown that deletion of KLF10 rescues cancer-induced muscle wasting. Moreover, KLF10 has also been shown to bind key atrophy genes associated with muscle atrophy in vitro . There is an elevated need to explore targets in cachexia, which will successfully translate into the clinic. Investigating a convergence point downstream of multiple signaling pathways might hold promise in developing effective therapies for cachexia.