Search Results (2,256)

Corneal fibrosis is a major cause of visual impairment worldwide and is characterized by persistent stromal scarring that disrupts corneal transparency. Although transforming growth factor-β (TGF-β)-mediated myofibroblast differentiation is well established, the mechanisms that sustain myofibroblast survival and persistence remain poorly understood. In this study, we investigated the role of the insulin-like growth factor (IGF) signaling axis in corneal myofibroblast survival and evaluated the therapeutic potential of linsitinib, a dual IGF-1 receptor (IGF-1R)/insulin receptor (INSR) inhibitor. Primary corneal myofibroblasts were exposed to pro-apoptotic conditions and treated with IGF ligands in the presence or absence of linsitinib. The effects of IGF pathway inhibition were further examined in a mouse model of corneal fibrosis. IGF-1 and IGF-2 promoted myofibroblast survival under pro-apoptotic conditions, whereas pharmacologic inhibition of IGF-1R/INSR signaling with linsitinib blocked these pro-survival effects. In vivo, linsitinib treatment reduced myofibroblast persistence and attenuated corneal fibrosis. These findings identify the IGF axis as a critical regulator of corneal myofibroblast survival and suggest that persistent fibrosis is maintained, in part, by IGF-dependent resistance to apoptosis. Targeting survival pathways rather than myofibroblast differentiation may represent a novel therapeutic strategy for the treatment of corneal fibrosis. Full article

Introduction: IgA nephropathy (IgAN) is a leading cause of end-stage renal disease. Given the significant adverse effects and inconsistent long-term efficacy of conventional immunosuppressive strategies, there is an unmet need for safer adjunctive therapies. Omega-3 polyunsaturated fatty acids (PUFAs) have been proposed as potential candidates to address this therapeutic gap. Purpose: This narrative review summarizes the proposed mechanisms of action of omega-3 PUFAs in IgAN and critically evaluates the current clinical evidence regarding their therapeutic potential and limitations. Mechanisms: Emerging experimental data suggest that omega-3 PUFAs may modulate inflammatory and fibrotic pathways relevant to kidney injury. Proposed mechanisms include modulation of eicosanoid metabolism, attenuation of NLR family pyrin domain-containing 3 (NLRP3) inflammasome activation, and generation of specialized pro-resolving mediators. In experimental studies, omega-3 PUFAs may also suppress nuclear factor kappa B (NF-κB)-driven transcription and attenuate mesangial cell proliferation, IgA immune-complex deposition, and transforming growth factor beta 1 (TGF-β1)/Smad3-mediated fibrotic signaling. Clinical Evidence: Conclusions: Omega-3 PUFAs have biological plausibility as adjunctive therapy in IgAN, but their clinical benefit remains uncertain. Available randomized trials and meta-analyses suggest possible modest effects on proteinuria in some settings, whereas evidence for preservation of kidney function or prevention of kidney failure is inconsistent and of low certainty. Future well-designed trials incorporating guideline-directed background therapy and biomarker-guided patient selection are essential to determine optimal dosing, formulation, biological exposure, and whether any patient subgroups derive clinically meaningful benefit. Full article

Excessive ultraviolet A (UVA) irradiation disrupts extracellular matrix (ECM) homeostasis in skin photoaging by impairing the balance between synthesis and degradation, yet whether silk fibroin peptide (SF), a small bioactive peptide from Bombyx mori, can restore this balance through mechanotransduction pathways remains unknown. Herein, we demonstrate that SF dose-dependently rescues human dermal fibroblasts (HDFs) from UVA-induced oxidative stress, senescence, and ECM disintegration. Notably, SF not only suppresses reactive oxygen species (ROS) and restores activities of antioxidant enzymes, but is also associated with the recovery of the ITGB1-FAK mechanotransduction axis, as evidenced by restored fibronectin levels and increased focal adhesion kinase (FAK) phosphorylation, whereas integrin β1 (ITGB1) expression itself was not significantly altered. This mechanosensory recovery is accompanied by restoration of downstream transforming growth factor-β (TGF-β)/Smad signaling, upregulation of COL1A1, COL3A1 and ELN transcription, and simultaneous suppression of MMP1, MMP3 and MMP9. Unlike conventional antioxidants or exogenous collagen supplements that merely counteract oxidative damage or provide structural substitutes, SF may facilitate recovery of the disrupted cell–matrix interface potentially through modulation of integrin-mediated mechanochemical signal conversion, which may contribute to ECM homeostasis restoration. Collectively, SF promotes mechanotransduction, offering a potential paradigm for anti-aging strategies that target ECM homeostasis through integrin signaling. Full article

Oral submucous fibrosis (OSMF) is a chronic, progressive fibrotic disorder with significant malignant potential, and limited effective treatments due to an incomplete understanding of its underlying molecular mechanisms. This narrative review synthesizes current evidence on the key molecular networks involved in OSMF pathogenesis, highlighting the central role of the TGF-β1/Smad, CTGF, and COL1A1 pathways in maintaining fibroblast activation, supporting myofibroblast activity, and promoting pathological collagen accumulation. It also integrates recent findings on how profibrotic signaling interacts with important angiogenic and epithelial growth factors such as VEGF, FGF, and EGF, creating a stage-dependent fibrotic microenvironment. In early OSMF, increased angiogenic signaling, especially through the VEGF/PI3K–Akt pathway, helps maintain blood supply. However, as the disease progresses, TGF-β-induced pathways become dominant, leading to vascular rarefaction, tissue hypoxia, epithelial instability and worsening fibrosis that increases the risk of malignant transformation. By critically appraising molecular, cellular, and translational studies, this review identifies key pathways linking fibrosis, angiogenesis, and epithelial changes in OSMF. It suggests that stage-specific and combined targeting of TGF-β1, CTGF, COL1A1, along with angiogenic and epithelial pathways, may help reverse fibrosis, restore normal tissue perfusion, reduce cancer risk, and support the development of better therapies and biomarkers beyond symptom relief. Full article

Erythropoiesis-targeted doping remains a major challenge for sports medicine because pharmacological and genetic manipulation of erythropoiesis can improve oxygen transport and endurance performance while increasing the risk of serious cardiovascular complications. Erythropoiesis-targeting strategies extend beyond recombinant erythropoietin (EPO) to include hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs), modified erythropoietin receptor (EPOR) agonists, transforming growth factor beta (TGF-β) signaling inhibitors, cytoprotective EPO derivatives, and gene- or cell-based approaches, and require complementary detection strategies based on direct analytical methods and the Athlete Biological Passport (ABP). Although they may enhance oxygen delivery and endurance performance, excessive stimulation of erythropoiesis may increase blood viscosity, impair vascular function, and elevate the risk of hypertension, thromboembolic complications, and other cardiovascular (CV) events. Erythropoiesis-targeted doping has evolved beyond recombinant EPO into a diverse group of pharmacological and genetic strategies that require increasingly sophisticated detection approaches. A thorough understanding of their molecular mechanisms and cardiovascular consequences is essential for improving anti-doping surveillance and protecting athlete health. This review summarizes current erythropoiesis-targeting agents, their mechanisms of action, detection strategies, cardiovascular risks, and implications for anti-doping practice. Full article

The renin–angiotensin–aldosterone system (RAAS) is a fundamental regulator of blood pressure, electrolyte balance, fluid homeostasis, and tissue remodeling. The discovery of the prorenin receptor (PRR), the protein encoded by the ATP6AP2 gene, has substantially expanded the classical RAAS paradigm by demonstrating that prorenin possesses biological activity beyond its proteolytic conversion to renin. Binding of renin or prorenin to PRR enhances local angiotensin II (Ang II) generation while simultaneously initiating Ang II-independent intracellular signaling pathways, including ERK1/2, mitogen-activated protein kinases, PI3K/Akt, transforming growth factor-β, and nuclear factor-κB, thereby promoting inflammation, oxidative stress, fibrosis, cellular proliferation, and extracellular matrix accumulation. Beyond its receptor function, PRR serves as an essential accessory component of the vacuolar H+-ATPase (V-ATPase) complex, regulating vesicular acidification, lysosomal function, autophagy, protein trafficking, cellular metabolism, and Wnt/β-catenin signaling. These diverse functions explain its indispensable role in embryonic development, cell differentiation, and tissue homeostasis, as evidenced by the embryonic lethality associated with ATP6AP2 gene deficiency. PRR is predominantly localized to intracellular organelles, including the endoplasmic reticulum, Golgi apparatus, endosomes, lysosomes, and autophagic vesicles, although membrane-bound and soluble forms also contribute to physiological and pathological processes. Increasing evidence implies dysregulated PRR signaling in the development and progression of hypertension, cardiovascular disease, chronic kidney disease, diabetes, obesity, and other metabolic disorders. This review summarizes current advances in PRR and soluble PRR biology, discusses unresolved mechanistic and translational questions, and evaluates the potential of PRR as a biomarker and therapeutic target for cardiovascular, renal, and metabolic diseases. Full article

RARγ is expressed during embryogenesis by stem/primitive progenitor cells, indicating a role in controlling their development. Supporting this view is that a physiological level of 10 nM of the RARγ agonist AGN205327 blocked stem/progenitor cell differentiation during zebrafish embryogenesis, mouse gastruloid development, and adult chondro- and osteogenesis. Similarly, transgene expression of RARγ or the use of the RARγ agonist CD437 enhanced the generation of induced pluripotent stem cells (iPSCs) from human and mouse somatic cells. RARγ regulates many events that control the behavior of stem/progenitor cells regarding whether they develop to give rise to mature cells. RARγ positively regulates the expressions of NOTCH ligands and their receptors, transforming growth factors (TGFs), and molecules pertaining to cell identity, extracellular matrix communication, and all-trans retinoic acid synthesis and catabolism. The genes that are repressed by RARγ include RARγ, PPARγ, and RXRα. RARγ integrates into Wnt/β-catenin and TGFβ signaling by acting as a co-factor to the gene co-activator β-catenin and transcription factor Smad3, respectively. Within the cytoplasm, RARγ regulates Akt/NF-κB signaling. As a model, we propose that ATRA ligand-activated RARγ acts as a gatekeeper to stem cell developmental progression during embryogenesis and that this role extends to stem/progenitor cell homeostasis within adult tissues. Full article

The lack of effective anti-fibrotic agents remains a significant unmet need in the treatment of intestinal fibrosis, a condition largely driven by transforming growth factor-β1 (TGF-β1)-mediated myofibroblast activation. Phosphodiesterase 4 (PDE4) inhibitors, known to increase intracellular cAMP levels, exhibit anti-inflammatory and potential anti-fibrotic properties, though their efficacy in intestinal fibrosis is poorly defined. In this study, we investigated the anti-fibrotic effects and underlying mechanisms of PDE4 inhibitors (rolipram, roflumilast, piclamilast, and mesopram) in human intestinal myofibroblasts (HIMFs) stimulated with TGF-β1. All PDE4 inhibitors significantly reduced TGF-β1-induced mRNA expression of collagen1A1 (COL1A1) and fibronectin (FN1), with mesopram additionally reducing α-smooth muscle actin (ACTA2) mRNA expression. At the protein level, however, only roflumilast significantly decreased procollagen1A1 (Procol1A1) and FN expression. Mechanistically, roflumilast, rolipram, and mesopram significantly reduced serum response factor (SRF) mRNA expression, whereas piclamilast and mesopram significantly inhibited myocardin-related transcription factor A (MRTFA) mRNA expression. Rolipram and roflumilast exhibited a decreasing trend in MRTFA mRNA expression without statistical significance. Notably, roflumilast demonstrated superior inhibitory effects, significantly decreasing both MRTF-A and SRF protein expression and effectively reducing nuclear localization of MRTF-A. Additionally, rolipram and roflumilast significantly attenuated TGF-β1-induced phosphorylation of Smad2. These findings indicate that PDE4 inhibitors, particularly roflumilast, effectively suppress TGF-β1-induced fibrogenic activation in HIMFs by modulating MRTF/SRF and Smad-dependent pathways, highlighting the value of roflumilast for further preclinical investigation as a potential therapeutic strategy for intestinal fibrosis. Full article

Peripheral T-cell lymphomas (PTCLs) are a heterogeneous group of clinically aggressive mature T-cell and natural killer (NK)-cell neoplasms that account for approximately 10–15% of all non-Hodgkin lymphomas in Western countries . The most common subtypes include extranodal NK/T-cell lymphoma (ENKTL), nodal T-follicular helper cell lymphomas, peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS), anaplastic large cell lymphoma (ALK-positive and ALK-negative), and T-cell lymphoblastic lymphoma. Non-coding RNAs (ncRNAs) constitute the majority of the human transcriptome and play critical roles in regulating gene expression, cellular proliferation, differentiation, migration, and apoptosis. Among these, long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs) have emerged as key regulators of lymphomagenesis and disease progression in PTCLs. These molecules modulate diverse oncogenic pathways through chromatin remodeling, transcriptional regulation, competing endogenous RNA activity, and interactions with RNA-binding proteins, thereby influencing proliferation, immune evasion, treatment resistance, and clinical outcomes. Representative examples include the lncRNA TCLlnc1, which promotes PTCL progression through activation of transforming growth factor-β (TGF-β) signaling, and the circRNAs circKIF4A, circADARB1, and circ-LAMP1, which regulate miRNA-dependent signaling networks involving PDK1/BCL11A, STAT3, and DDR2, respectively. In this review, we summarize the current understanding of the biological and clinical roles of lncRNAs and circRNAs in PTCL and related T-cell and NK-cell neoplasms and highlight their potential as diagnostic and prognostic biomarkers as well as therapeutic targets. We also discuss recent advances and future directions for integrating ncRNA-based approaches into precision medicine for T-cell lymphoma. Full article

Cool-climate maize fields are characterized by low soil temperatures, strong seasonal hydrothermal fluctuations, and peat-influenced soil profiles, which may lead to patterns of nitrogen (N) cycling distinct from those in conventional agricultural soils. During maize growth, soils from three depths were characterized using physicochemical measurements, N-transformation and enzyme-activity assays, metagenomic sequencing, Mantel tests, variation partitioning analysis, and partial least squares path modeling (PLS-PM). Soil environmental factors varied significantly over time and with depth; soil organic matter (SOM) and total nitrogen (TN) increased with depth, while ammonium nitrogen (NH₄⁺-N) predominated early and nitrate nitrogen (NO₃⁻-N) predominated during the middle and late growth stages. The nitrogen fixation rate (NFR), nitrification rate (NitR), and denitrification rate (DNR) all peaked in August and showed a spatial pattern characterized by nitrogen fixation in the deepest layer and denitrification in the upper and middle layers. Bacterial communities varied less spatiotemporally than fungal communities. The genes nifK, hao, nirS/nirK, NR, nrfC, and hzsA/hzsC were identified as key nitrogen-cycling functional genes. Mantel tests and PLS-PM further characterized these relationships, with PLS-PM showing that soil physicochemical properties were positively associated with bacterial community composition (β = 0.87, p < 0.01), which, in turn, was negatively associated with N-cycling functional genes (β = −0.97, p < 0.001). Together, these pathways were associated with variation in N-cycling processes. Overall, this study advances an integrated understanding of N-cycling patterns and their potential controls in cool-climate maize fields and provides a scientific basis for optimizing N management strategies. Full article

Cardiac fibrosis is a hallmark of pathological cardiac remodeling, characterized by fibroblast activation, excessive extracellular matrix deposition, and myocardial hypertrophy, ultimately leading to cardiac dysfunction. Aging exacerbates these processes through metabolic stress and impaired mitochondrial bioenergetics. Here, we investigated the anti-fibrotic effects of metformin and the role of fatty acid β-oxidation (FAO) in regulating cardiac fibroblast differentiation. Metformin significantly attenuated transforming growth factor-β (TGF-β)-induced cardiac fibroblast activation and the associated senescence-like phenotype. These effects were accompanied by enhanced FAO and increased mitochondrial oxygen consumption rate (OCR), indicating improved mitochondrial function. Importantly, inhibition of carnitine palmitoyltransferase-1 (CPT1) with etomoxir largely abolished the beneficial effects of metformin on mitochondrial respiration, fibroblast activation, and cellular senescence, demonstrating a critical role for FAO. Mechanistically, metformin increased CPT1 activity and acetyl-CoA levels while reducing malonyl-CoA accumulation, thereby promoting mitochondrial fatty acid utilization. These findings were corroborated in aged Apoe^−/− mice, where metformin reduced the expression of cardiac fibroblast differentiation markers and enhanced FAO-associated markers. Collectively, our findings demonstrate that metformin suppresses cardiac fibroblast differentiation and senescence by preserving mitochondrial bioenergetics through FAO-dependent mechanisms, revealing a metabolic basis for its anti-fibrotic actions and supporting its therapeutic potential in age-related cardiovascular disease. Full article

Background: Dangguibuxue decoction (DD), containing Angelica sinensis (Oliv.) Diels (AS) and Astragalus membranaceus (Fisch.) Bge. (AM) (1:5), is a well-known traditional Chinese medicine (TCM) used for strengthening qi and nourishing the blood. DD has shown therapeutic effects in nephropathy patients. However, the underlying mechanisms based on the traditional efficacy are still not fully elucidated. Methods: The chemical constituents in DD were identified using UPLC-MS/MS. Network pharmacology analysis was applied to predict the potential target genes and associated signaling pathways. A renal fibrosis mouse model was induced by the intraperitoneal injection of aristolochic acid I (AA I) at 3.0 mg/kg. Mice were treated with AM, AS, and DD at two dosages by oral gavage for 30 days. Body weights, serum biochemistry, hematology, and histopathology observations were assessed. The key targets predicted were validated using qRT-PCR and Western blotting. The active constituents were screened by molecular docking, and their anti-fibrotic effects were evaluated through in vitro assays. Results: DD effectively improved renal functions and alleviated AA I-induced renal fibrosis. DD alleviated anemia and upregulated the expression of Erythropoietin (EPO). Network pharmacology analysis indicated the involvement of signaling pathways, including the PI3K/Akt, hypoxia-inducible factor-1α (HIF-1α) and transforming growth factor-β (TGF-β) signaling pathways. Experimental validation further demonstrated that DD reduced the protein expression of HIF-1α, collagen I, and TGF-β, and the ratios of phosphorylated Smad2/3 to total Smad2/3. Molecular docking and in vitro assays suggested that rutin may be a potential bioactive compound in DD. Conclusions: This research indicated that DD ameliorated AA I-induced renal fibrosis in mice, which may be associated with the modulation of HIF-1α and TGF-β/Smad signaling pathways. Rutin may be a potential bioactive compound in DD with anti-fibrotic activity, but further studies are still needed to clarify the content of rutin in DD, the amount of its exposure in the body, and its contribution to the effects of DD. Full article

Background/Objectives: Isorhamnetin is a naturally occurring flavonoid with reported antioxidant, anti-inflammatory, and anticancer properties. Although its biological activities have been extensively investigated, its effects on ovarian cell physiology remain insufficiently characterized. This study aimed to evaluate the influence of isorhamnetin on the viability, steroid hormone secretion, apoptosis, and growth factor signalling in human ovarian cell lines representing both non-tumour and tumour phenotypes. Methods: Human granulosa (HGL5), granulosa tumour (COV434), and epithelial ovarian carcinoma (OVCAR-3) cell lines were treated with isorhamnetin at concentrations of 5–80 μg/mL for 24 h. Cell viability was determined using the AlamarBlue^TM assay. The secretion of progesterone, 17β-estradiol, and the presence of transforming growth factor β2 (TGF-β2), transforming growth factor β receptor 2 (TGFBR2), and apoptosis-inducing factor (AIF) was quantified by enzyme-linked immunosorbent assay (ELISA). Results: Isorhamnetin significantly reduced cell viability in a dose-dependent manner, with tumour cell lines exhibiting greater sensitivity than non-tumour granulosa cells. A significant decrease in viability was observed in OVCAR-3 cells from 10 μg/mL onward, whereas COV434 cells showed significant reductions at concentrations of 20 μg/mL and higher. In contrast, HGL5 cell viability was significantly affected only at the highest concentration (80 μg/mL). No significant changes were detected in the secretion of progesterone, 17β-estradiol, TGF-β2, or TGFBR2 in any of the examined cell lines. A significant reduction in AIF production was observed only in HGL5 cells treated with 80 μg/mL isorhamnetin. Conclusions: Isorhamnetin preferentially decreased the viability of ovarian tumour cells while exerting only limited effects on non-tumour granulosa cells, indicating preferential cytotoxic activity toward malignant ovarian cells. The absence of significant changes in steroid hormone production and TGF-β suggests that its antiproliferative effects involve molecular pathways that were not investigated in the present study. These findings support further investigation of isorhamnetin as a potential natural compound for ovarian cancer prevention or adjunctive therapy. Full article

Decorin, a proteoglycan shown to inhibit transforming growth factor β1 (TGF-β1) signaling, has been increasingly considered as a potential anti-fibrotic agent to aid in therapies addressing corneal scarring and blindness. Decorin is also known to interact with a wide range of other growth factors, such as platelet-derived growth factor (PDGF), which has been shown to stimulate corneal cell migration to repopulate the decellularized region of the wounded cornea. In other tissues, decorin has been shown to inhibit PDGF-mediated migration and prolong wound healing. However, our understanding of the effect of decorin on PDGF signaling in the corneal stroma environment is limited. Specifically, thus far, there have been no studies investigating the interaction between decorin and PDGF in the context of the uniquely organized fibrillar collagen extracellular matrix (ECM), which provides topographic cues that guide cell migration during wound healing. The purpose of this study is to use an in vitro model of decorin-coated aligned collagen fibrils analogous to the corneal stroma ECM to investigate this interaction. With this in vitro model, we demonstrate that decorin inhibits the response of PDGF-BB-stimulated keratocytes to a 2-dimensional (2D) aligned collagen fibril ECM, reducing cell alignment, motility, PDGF receptor β (PDGFRβ) phosphorylation, and wound closure. We observed that when presented with a decellularized wound region, cells on the decorin-coated substrates migrated more randomly and were less aligned with the underlying aligned collagen fibrils than cells on uncoated fibrils, resulting in slower wound closure. Furthermore, PDGF-BB-stimulated cells on the decorin coating had increased branching and reduced solidity, representing a shift from the elongated, bipolar morphology typically resulting from PDGF-BB treatment towards the stellate, branched keratocyte phenotype. While decorin seems to be an effective agent against TGF-β1-mediated fibrosis, its interaction with PDGF-BB appears to present other challenges to wound healing that should be considered in the development of therapies for healthy corneal wound healing. Full article

Sickle cell disease (SCD) is a globally distributed hereditary red cell disorder with still high mortality. Growing evidence indicates that sickle cell related cardiovascular disease contributes to the early death of adults with SCD. Here, we show that humanized SCD mice developed an age-dependent cardiomyopathy characterized by (i) increased circulating Th17 lymphocytes, Th17 heart infiltration associated with increased plasma IL-17; (ii) collagen deposition and activation of both platelet derived growth factor-B (PDGF-B) and transforming growth factor-β1 (TGF-β1) canonical pathways; (iii) overactivation of heart NF-κB associated with up-regulation of NLRP3 and of inflammatory vasculopathy markers. We then used colchicine (CLC) that acts as anti-inflammatory drug with immunomodulatory effects. In humanized SCD mice, we demonstrated the protective role of low-dose CLC treatment against chronic inflammation and preserving myocardial performance. Of note, we found CLC also attenuating sickle cell related lung damage, suggesting a multiorgan effect of CLC in SCD mice. Our data generate the rationale to further explore CLC as new therapeutic tool to treat early stages of sickle cell cardiomyopathy. Full article