Search Results (1,418)

MicroRNA-211 (miR-211) is a versatile regulatory molecule that plays critical roles in cellular homeostasis and disease progression through the post-transcriptional regulation of gene expression. This review comprehensively examines miR-211’s multifaceted functions across various biological systems, highlighting its context-dependent activity as both a tumor suppressor and oncogene. In physiological contexts, miR-211 regulates cell cycle progression, metabolism, and differentiation through the modulation of key signaling pathways, including TGF-β/SMAD and PI3K/AKT. miR-211 participates in retinal development, bone physiology, and protection against renal ischemia–reperfusion injury. In pathological conditions, miR-211 expression is altered in various diseases, particularly cancer, where it may be a useful diagnostic and prognostic biomarker. Its stability in serum and differential expression in various cancer types make it a promising candidate for non-invasive diagnostics. The review also explores miR-211’s therapeutic potential, discussing both challenges and opportunities in developing miRNA-based treatments. Understanding miR-211’s complex regulatory interactions and context-dependent functions is crucial for advancing its clinical applications for diagnosis, prognosis, and targeted therapy in multiple diseases. Full article

Background: Localized scleroderma (LoS) is a chronic autoimmune condition marked by cutaneous fibrosis and persistent inflammation. Modulating the activation of inflammatory cells and fibroblasts remains a central strategy in LoS treatment. We investigate the anti-fibrotic effects of Annexin A5 (AnxA5), identified as a key inflammatory component in fat extract, and assess its therapeutic efficacy. Methods: In vitro experiments were performed using TGF-β-stimulated primary human dermal fibroblasts treated with recombinant AnxA5. The anti-fibrotic effects and underlying mechanisms were assessed using CCK-8 assays, quantitative real-time PCR, Western blotting, and immunocytochemistry. In vivo, AnxA5 was administered via both preventative and therapeutic protocols in bleomycin-induced LoS mouse models. Treatment outcomes were evaluated by histological staining, collagen quantification, immunostaining, and measurement of pro-inflammatory cytokines. Results: TGF-β stimulation induced myofibroblast differentiation and extracellular matrix (ECM) production in dermal fibroblasts, both of which were significantly attenuated by AnxA5 treatment through the inhibition of phosphorylation of Smad2. In vivo, both preventative and therapeutic administration of AnxA5 effectively reduced dermal thickness, collagen deposition, ECM accumulation, M1 macrophage infiltration, and levels of pro-inflammatory cytokines. Conclusions: Through both preventative and therapeutic administration, AnxA5 ameliorates LoS by exerting dual anti-fibrotic and anti-inflammatory effects, underscoring its potential for treating fibrotic diseases. Full article

Transforming growth factor-β (TGF-β) is a key protein family member that includes activins, inhibins, and bone morphogenetic proteins (BMPs). It is essential in numerous biological processes, such as chemotaxis, apoptosis, differentiation, growth, and cell migration. TGF-β receptors initiate signaling through two primary pathways: the canonical pathway involving Smad proteins and non-canonical pathways that utilize alternative signaling mechanisms. When TGF-β signaling is disrupted, it has been shown to contribute to the development of various diseases, including cancer. Initially, TGF-β effectively inhibits the cell cycle and promotes apoptosis. However, its role can transition to facilitating tumor growth and metastasis as the disease progresses. Moreover, TGF-β drives cancer progression through epithelial–mesenchymal transition (EMT), modulation of factor expression, and evasion of immune responses. This complexity establishes the need for further research, particularly into pharmacological agents targeting TGF-β, which are emerging as promising therapeutic options. Current clinical and preclinical studies are making significant strides toward mitigating the adverse effects of TGF-β. This underscores the critical importance of understanding its underlying mechanisms to enhance treatment effectiveness and improve survival rates for cancer patients. Full article

Appendage autotomy frequently occurs during the cultivation of Exopalaemon carinicauda, which severely impacts its survival and economic benefits. To investigate the molecular mechanism underlying appendage regeneration in E. carinicauda, this study presents a comparative transcriptome analysis on samples from different stages of appendage regeneration in individuals of the same family of E. carinicauda. A total of 6460 differentially expressed genes (DEGs) were identified between the samples collected at 0 h post-autotomy (D0) and those collected at 18 h post-autotomy (D18h). Additionally, 7740 DEGs were identified between D0 and 14 d post-autotomy (D14d), with 3382 DEGs identified between D18h and D14d. Among them, differentially expressed genes such as EcR, RXR, BMP1, and Smad4 are related to muscle growth or molting and may be involved in the regeneration process. qRT-PCR results revealed that EcBMPR2 was expressed at relatively high levels in the gonad and ventral nerve cord tissues and that the highest level of expression was detected in the regenerative basal tissue at 24 h post-autotomy. In situ hybridization results indicated strong signals of this gene in the cells at the wound site at 72 h post-autotomy. Following knockdown of EcBMPR2, the expression levels of both EcBMPR1B and EcSmad1 were significantly downregulated, and long-term interference with the EcBMPR2 gene resulted in a significantly slower appendage regeneration process compared to the control group. When the downstream transcription factor EcSmad1 was knocked down, the two receptor genes EcBMPR2 and EcBMPR1B were downregulated, whereas EcBMP7 was upregulated. After inhibiting the BMP signaling pathway, the degree of cell aggregation at the autotomy site in the experimental group was significantly lower than that in the control group, the wound healing rate was delayed, and the blastema regeneration time was prolonged from 5 d to 7 d. Collectively, these results indicate that the BMP signaling pathway plays a critical role in the early stages of appendage regeneration in E. carinicauda. This study provides important theoretical insights for understanding limb regeneration in crustaceans. Full article

Non-small cell lung cancer (NSCLC) is a predominant form of lung cancer that is often diagnosed at an advanced metastatic stage. The processes of cancer cell migration and invasion involve epithelial-to-mesenchymal transition (EMT), which is crucial for metastasis. Targeting cancer aggressiveness with effective plant compounds has gained attention as a potential adjuvant therapy. Eurycomanone (ECN), a bioactive quassinoid found in the root of Eurycoma longifolia Jack, has demonstrated anti-cancer activity against various carcinoma cell lines, including human NSCLC cells. This study aimed to investigate the in vitro effects of ECN on the migration and invasion of human NSCLC cells and to elucidate the mechanisms by which ECN modulates the EMT in these cells. Non-toxic doses (≤IC20) of ECN were determined using the MTT assay on two human NSCLC cell lines: A549 and Calu-1. The results from wound healing and transwell migration assays indicated that ECN significantly suppressed the migration of both TGF-β1-induced A549 and Calu-1 cells. ECN exhibited a strong anti-invasive effect, as its non-toxic doses significantly suppressed the TGF-β1-induced invasion of NSCLC cells through Matrigel and decreased the secretion of MMP-2 from these cancer cells. Furthermore, ECN could affect the TGF-β1-induced EMT process in various ways in NSCLC cells. In TGF-β1-induced A549 cells, ECN significantly restored the expression of E-cadherin by inhibiting the Akt signaling pathway. Conversely, in Calu-1, ECN reduced the aggressive phenotype by decreasing the expression of the mesenchymal protein N-cadherin and inhibiting the TGF-β1/Smad pathway. In conclusion, this study demonstrated the anti-invasive activity of eurycomanone from E. longifolia Jack in human NSCLC cells and provided insights into its mechanism of action by suppressing the effects of TGF-β1 signaling on the EMT program. These findings offer scientific evidence to support the potential of ECN as an alternative therapy for metastatic NSCLC. Full article

Estrogens regulate many physiological processes in the human body, including the cardiovascular system. Importantly, Estradiol (E2) exerts its vascular protective actions, in part, by promoting endothelial repair via induction of endothelial cell (EC) proliferation, migration and angiogenesis. Recent evidence that microRNAs (miRNAs) play an important role in vascular health and disease as well as in regulating Estrogen actions in many cell types. We hypothesize that E2 may mediate its vascular protective actions via the regulation of miRNAs. Following initial screening, we found that E2 downregulates the levels of miR-193a-3p in ECs. Moreover, miR-193a-3p downregulation by miR-193a-3p-antimir mimicked the effects as E2 on EC growth, migration, and capillary formation. Restoring miR-193a-3p levels with mimics after E2 treatment abrogated the vasculogenic actions of E2, suggesting a key role of miR-193a-3p in E2-mediated EC-growth-promoting effects. We further investigated the cellular mechanisms involved and found that miR-193a-3p inhibits angiogenesis by blocking phosphoinositide-3-kinase (PI3K)/Akt-vascular endothelial growth factor (VEGF) and Activin receptor-like kinase 1 (ALK1)/SMAD1/5/8 signaling in ECs, both pathways that are important in E2-mediated vascular protection. Additionally, using reverse transcription polymerase chain reaction (RT-PCR), we demonstrate that E2 downregulates miR-193a-3p in ECs via Estrogen Receptor (ER)α, but not ERβ or G protein-coupled estrogen receptor (GPER). Moreover, these actions occur post-transcriptionally, as the expression of pri-miR-193a-3p was not affected. The anti-angiogenic actions of miR-193a-3p were also observed in in vivo Matrigel implant-based capillary formation studies in ovariectomized mice where E2 induced capillary formation, and these effects were abrogated in the presence of miR-193a-3p, but not in the control mimic. Assessment of miR-193a-3p levels in plasma collected from in vitro fertilization (IVF) subjects with low and high E2 levels showed significantly lower miR-193a-3p levels in responders during the high E2 period. Hence, our findings provide the first evidence that miR-193a-3p mimic inhibits angiogenesis whereas its antimir is angiogenic. Importantly, E2 mediates its regenerative actions on ECs/capillary formation by downregulating endogenous miR-193a-3p expression. Both miR-193a-3p mimic or antimir may represent important therapeutic molecules to prevent or to induce endothelial function in treating pathophysiologies associated with capillary growth. Full article

Crohn’s disease (CD), characterized by chronic gastrointestinal inflammation, is complicated by intestinal stenosis resulting from dysregulated fibrogenesis and is marked by excessive extracellular matrix (ECM) deposition, fibroblast activation, and luminal obstruction. While biologics control inflammation, their failure to halt fibrosis underscores a critical therapeutic void. Emerging evidence highlights the multifactorial nature of stenosis-associated fibrosis, driven by profibrotic mediators and dysregulated crosstalk among immune, epithelial, and mesenchymal cells. Key pathways, including transforming growth factor (TGF-β), drosophila mothers against decapentaplegic protein (Smad) signaling, Wnt/β-catenin activation, epithelial–mesenchymal transition (EMT), and matrix metalloproteinase (MMP) and tissue inhibitors of metalloproteinase (TIMP)-mediated ECM remodeling, orchestrate fibrotic progression. Despite the current pharmacological, endoscopic, and surgical interventions for fibrostenotic CD, their palliative nature and inability to reverse fibrosis highlight an unmet need for disease-modifying therapies. This review synthesizes mechanistic insights, critiques therapeutic limitations with original perspectives, and proposes a translational roadmap prioritizing biomarker-driven stratification, combinatorial biologics, and mechanistically targeted antifibrotics. Full article

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disorder characterized by excessive scarring of lung tissue, predominantly affecting middle-aged and elderly populations. Oxidative stress plays a pivotal role in the pathogenesis of pulmonary fibrosis, disrupting redox homeostasis and driving fibrotic progression. Glutathione reductase (GSR), a key antioxidant enzyme, is essential for maintaining cellular glutathione (GSH) levels and mitigating oxidative damage. However, the specific involvement of GSR in IPF remains poorly understood. This study found that GSR levels were downregulated in IPF patients and mice treated with bleomycin (BLM). GSR knockdown enhanced epithelial-to-mesenchymal transition (EMT) in A549 cells and promoted the activation of MRC5 cells. Additionally, GSR depletion promoted cellular migration and senescence in both A549 and MRC5 cells. Mechanistically, silencing GSR in A549 and MRC5 cells led to a marked reduction in intracellular GSH levels, resulting in elevated reactive oxygen species (ROS) accumulation, thereby promoting the activation of the TGF-β/Smad2 signaling pathway. In conclusion, our findings demonstrate that GSR deficiency aggravates pulmonary fibrosis by impairing antioxidant defense mechanisms, promoting EMT, and activating fibroblasts through the TGF-β/Smad2 signaling. These findings suggest that GSR may be essential in reducing the fibrotic progression of IPF. Full article

Background: Increased IL-1β levels may promote carcinogenesis and metastasis by affecting tumor biology and the tumor microenvironment (TME). In this context, extracellular vesicles (EVs) play a key role in cell-to-cell communication, thus modulating the TME and immune response. Here, we aimed to test whether tumor-derived small EVs (TEVs) isolated from sensitive and osimertinib-resistant (OR) non-small-cell lung cancer (NSCLC) cells may promote EMT via fibronectin binding to α5β1 integrin as well as suppress the immune system and if these effects may be favored by IL-1β. Methods: TEVs were isolated from control, OR, and IL-1β-stimulated NSCLC cells. Expressions of fibronectin and PD-L1 were screened in TEVs and the mRNA levels of vimentin and SMAD3 were also assessed in cancer cells after TEV co-culturing. Furthermore, to detect the effect on immune cells, we co-cultured TEVs with lung cancer patients’ peripheral blood mononuclear cells (PBMCs). Results: TEVs were positive for fibronectin and the highest protein levels were found in TEVs obtained from the OR and IL-1β-stimulated cells. TEV-mediated activation of α5β1 signaling led to the upregulation of vimentin and SMAD3 mRNA in NSCLC cells and stimulated cell migration. EVs also increased PD-1, CTLA-4, FOXP3, TNF-α, IL-12, and INF-γ mRNA in lung cancer patients’ immune cells. Conclusions: Our findings indicate that TEVs promote EMT in NSCLC cells by the activation of the fibronectin–α5β1 axis. Finally, IL-1β stimulation induces TEV release with biological properties similar to OR TEVs, thus leading to cancer invasion and immune suppression and suggesting that inflammation can promote tumor spreading. Full article

Background: Pancreatic cancer is frequently identified as the cancer type with the shortest probable survival time after diagnosis, and efforts to develop successful treatments have had a very limited impact in the clinic. One reason for the limited therapeutic options is the lack of appealing drug targets. The great majority of pancreatic cancers are classified as Pancreatic Ductal Adenocarcinoma (PDAC), in which the genetic landscape is dominated by four genes: KRAS, TP53, CDKN2A, and SMAD4. However, despite extensive knowledge of these genetic drivers, the development of effective therapies has seen only very limited success. Methods: Existing evidence indicates that mutations in the tumour suppressor gene PTEN are uncommon in PDAC (<10% cases). However, the loss of PTEN function through non-genetic mechanisms may be much more common and have a strong impact. We therefore summarise and review a large body of immunohistochemical studies that address the loss of PTEN in PDAC as well as a smaller number of studies addressing other implicated proteins, including KDM6A and ARID1A. Results: These studies show some loss of PTEN protein in more than half of PDAC cases. Furthermore, although genetic changes in genes including KDM6A/UTX and ARID1A are also uncommon, reduced expression of their encoded proteins is observed in many, perhaps most, cases of PDAC. Conclusions: These analyses, which go beyond genetics, highlight the broader set of cellular functions that are dysregulated in many pancreatic cancers and provide broader opportunities for treatment strategies. This review highlights the emerging importance of other drivers in PDAC, which are less well-studied in this context. Full article

SUMOylation plays a crucial role in regulating gene expression by promoting interactions between transcription factors and corepressors. Daxx, a multifunctional scaffold protein, specifically recognizes and binds SUMOylated transcription factors through its SUMO-interacting motifs (SIMs), acting as a transcriptional corepressor. In this review, we systematically elucidate the structural basis of the interaction between Daxx and SUMO, revealing the synergistic mechanism by which Daxx SIM phosphorylation and SUMO acetylation dynamically regulate Daxx function. In promyelocytic leukemia nuclear bodies (PML NBs), phosphorylation of Daxx’s SIM enhances its binding to SUMOylated PML, leading to the sequestration and inactivation of Daxx within PML NBs. Conversely, SUMO acetylation disrupts the electrostatic interactions between SUMO and SIMs, prompting the release of Daxx from PML NBs and its translocation to the nucleoplasm, where it inhibits the activity of transcription factors such as ETS1, GR, and SMAD4. Daxx SIMs are common binding sites for the interaction between SUMOylated transcription factors and Daxx, and different SUMOylated transcription factors may compete to bind to Daxx, which cross-regulates cellular life activities. This mechanism highlights the dynamic regulation of Daxx subcellular localization and transcriptional repression by SUMO and PML NBs, providing valuable insights into understanding Daxx-mediated transcriptional repression. Full article

Wound healing involves complex interplay between cellular and molecular events. In this study, we investigated the therapeutic potential of the bovine amniotic membrane (BAM) in wound healing using a mouse model. Twelve male C57BL/6 mice were divided into four groups: negative control (Vehicle), positive control (DuoDERM Extra Thin^®), amniotic membrane attachment (Amniotic Membrane), and compressed amniotic membrane attachment (Amniotic Membrane with Compression). The dorsal skin of each mouse was excised and wound-healing parameters were assessed over a two-week period. Our results revealed that the Amniotic Membrane and Amniotic Membrane with Compression groups demonstrated significant sustained reductions in the wound area compared to the Vehicle group. These reductions were more pronounced than those observed in the DuoDERM group. Histopathological analysis revealed advanced wound healing characteristics in the BAM-treated groups. Immunohistochemical analysis demonstrated elevated expression levels of wound healing markers (including α-smooth muscle actin, collagen type III, SMAD 1/5/8, and SMAD 2/3) in the BAM-treated groups compared to the control and DuoDERM groups. Conversely, cluster of differentiation 4 levels were significantly lower in BAM-treated groups. Overall, our findings highlight the therapeutic efficacy of BAM and compression in promoting wound healing. Thus, BAM offers a promising therapeutic approach for enhancing wound healing outcomes in clinical settings, potentially by modulating key wound healing pathways and processes. Full article

Background: Diabetic lung disease, characterized by inflammation and fibrosis, is an emerging chronic complication of type 2 diabetes mellitus (T2DM). However, systematic studies on the effects of exercise interventions remain limited. This study aimed to investigate the impact of different exercise types (swimming, resistance training, and high-intensity interval training [HIIT]) on pulmonary inflammation and fibrosis in T2DM mice, and to explore underlying molecular mechanisms. Methods: A T2DM mouse model was established by a high-fat diet (HFD) combined with streptozotocin (STZ) induction. Mice were randomly divided into sedentary control, swimming, resistance training, and HIIT groups, and underwent 8 weeks of exercise intervention. After the intervention, body composition was assessed. Lung histopathological changes were evaluated by hematoxylin&eosin (HE) and Masson staining. Inflammatory cytokines, fibrosis markers, and the expression of the TGF-β1/Smad signaling pathway were detected. Macrophage infiltration and polarization were also analyzed. Results: Exercise intervention improved body composition and reduced oxidative stress in T2DM mice. All three exercise modalities downregulated inflammatory cytokine expression, inhibited macrophage activation and M1 polarization, and promoted M2 polarization. Additionally, exercise improved lung tissue structure, reduced collagen deposition, and decreased the expression of fibrosis-related markers. Furthermore, anti-fibrotic effects were mediated by suppression of the TGF-β1/Smad signaling pathway and inhibition of epithelial-mesenchymal transition (EMT). Among the interventions, HIIT demonstrated the strongest inhibitory effect on the TGF-β1/Smad pathway, while swimming showed the most significant anti-inflammatory benefits. Conclusions: Different types of exercise effectively alleviate pulmonary inflammation and fibrosis in T2DM mice. These effects are closely related to the inhibition of oxidative stress, regulation of macrophage polarization, and suppression of TGF-β1/Smad signaling activation, with swimming and HIIT demonstrating superior protective benefits. Full article

Background/Objectives: Treatment of locally advanced rectal cancer (LARC) very often requires a neoadjuvant multimodal approach. Neoadjuvant treatment (NAT) encompasses treatments like chemoradiotherapy (CRT), short-course radiotherapy (SCRT), radiotherapy (RT) or a combination of either of these two with additional induction or consolidation chemotherapy, namely total neoadjuvant treatment (TNT). In case of complete radiological and clinical response, the non-operative watch-and-wait strategy can be adopted in selected patients. This strategy is impacted by a regrowth rate of approximately 30%. Predicting biomarkers of tumor response to NAT could improve guidance of clinicians during clinical decision making, improving treatment outcomes and decreasing unnecessary treatment exposure. To this day, there is no validated biomarker to predict tumor response to any NAT strategies in clinical use. Most research focused on CRT neglects the study of other regimens. Methods: We conducted a narrative literature review which aimed at summarizing the status of biomarkers predicting tumor response to NAT other than CRT in LARC. Results: Two hundred and fourteen articles were identified. After screening, twenty-one full-text articles were included. Statistically significant markers associated with improved tumor response pre-treatment were as follows: low circulating CEA levels; BCL-2 expression; high cellular expression of Ku70, MIB-1(Ki-67) and EGFR; low cellular expression of VEGF, hPEBP4 and nuclear β-catenin; the absence of TP53, SMAD4, KRAS and LRP1B mutations; the presence of the G-allel of LCS-6; and MRI features such as the conventional biexponential fitting pseudodiffusion (Dp) mean value and standard deviation (SD), the variable projection Dp mean value and lymph node characteristics (short axis, smooth contour, homogeneity and Zhang et al. radiomic score). In the interval post-treatment and before surgery, significant markers were as follows: a reduction in the median value of circulating free DNA, higher presence of monocytic myeloid-derived suppressor cells, lower presence of CTLA4+ or PD1+ regulatory T cells and standardized index of shape changes on MRI. Conclusions: Responders to neoadjuvant SCRT and RT tended to have a tumor microenvironment with an immune–active phenotype, whereas responders to TNT tended to have a less active tumor profile. Although some biomarkers hold great promise, scarce publications, inconsistent results, low statistical power, and low reproducibility prevent them from reliably predicting tumor response following NAT. Full article

The transforming growth factor-beta (TGF-β) superfamily plays a crucial role in regulating female reproductive traits, particularly litter size, in small ruminants, such as sheep and goats. This review comprehensively examines the molecular mechanisms through which TGF-β superfamily members—including bone morphogenetic proteins (BMPs), growth differentiation factor 9 (GDF9), inhibin (INHA and INHB), and associated signaling genes—influence ovarian follicular development, ovulation rate, and ultimately, litter size. We synthesize recent findings on polymorphisms in key genes, such as BMPR1B, BMP15, GDF9, inhibins and SMADs family genes, across diverse sheep and goat breeds worldwide. The manuscript highlights how specific mutations in these genes create an intricate signaling network that modulates granulosa cell proliferation, follicular sensitivity to FSH, and the prevention of dominant follicle selection. These molecular interactions result in increased ovulation rates and larger litter sizes in prolific breeds. The gene dosage effects observed in heterozygous versus homozygous mutation carriers further illuminate the complex nature of these reproductive regulations. This improved the understanding of the genetic basis for prolificacy provides valuable insights for marker-assisted selection strategies aimed at enhancing reproductive efficiency in small ruminant breeding programs, with significant implications for improving livestock productivity and economic outcomes. Full article