Detachable Microneedle Patch for Local Delivery of TGF-β Inhibitor to Suppress Scar Formation.

TGF‐β and smad signalling in fibrosis

Discoidin Domain Receptor 2–microRNA 196a–Mediated Negative Feedback against Excess Type I Collagen Expression Is Impaired in Scleroderma Dermal Fibroblasts

The metazoan liver exhibits a remarkable capacity to regenerate lost liver mass without leaving a scar following partial hepatectomy (PH). Whilst previous studies have identified components of several different signaling pathways that are essential for activation of hepatocyte proliferation during liver regeneration, the mechanisms that enable such regeneration to occur without accompanying scar formation remain poorly understood. Here we use the adult zebrafish liver, which can regenerate within two weeks following PH, as a new genetic model to address this important question. We focus on the role of Digestive-organ-expansion-factor (Def), a nucleolar protein which has recently been shown to complex with calpain3 (Capn3) to mediate p53 degradation specifically in the nucleolus, in liver regeneration. Firstly, we show that Def expression is up-regulated in the wild-type liver following amputation, and that the defhi429/+ heteroozygous mutant (def+/−) suffers from haploinsufficiency of Def in the liver. We then show that the expression of pro-inflammatory cytokines is up-regulated in the def+/− liver, which leads to distortion of the migration and the clearance of leukocytes after PH. Transforming growth factor β (TGFβ) signalling is thus activated in the wound epidermis in def+/− due to a prolonged inflammatory response, which leads to fibrosis at the amputation site. Fibrotic scar formation in def+/− is blocked by the over-expression of Def, by the loss-of-function of p53, and by treatment with anti-inflammation drug dexamethasone or TGFβ-signalling inhibitor SB431542. We finally show that the Def- p53 pathway suppresses fibrotic scar formation, at least in part, through the regulation of the expression of the pro-inflammatory factor, high-mobility group box 1. We conclude that the novel Def- p53 nucleolar pathway functions specifically to prevent a scar formation at the amputation site in a normal amputated liver.

Differential Contribution of Dermal Resident and Bone Marrow–Derived Cells to Collagen Production during Wound Healing and Fibrogenesis in Mice

IL-18 Downregulates Collagen Production in Human Dermal Fibroblasts via the ERK Pathway

A New Kid on the TGFβ Block: TAZ Controls Smad Nucleocytoplasmic Shuttling

Excessive collagen accumulation in dystrophic (mdx) respiratory musculature is independent of enhanced activation of the NF-κB pathway

Transforming growth factor receptor beta (TGF-β) signaling is commonly dysregulated in head and neck squamous cell carcinoma (HNSCC). TGF-β signaling influences homeostasis in normal epithelial cells and regulates a critical signaling network during development. In HNSCC, TGF-β signaling frequently promotes cell invasion, metastasis, proliferation, and drug resistance and may present an important therapeutic target. Canonical TGF-β signaling generally involves activation of SMAD effector proteins, most prominently SMAD2 and SMAD3, whereas noncanonical TGF-β signaling requires signal propagators including ERK, AKT, and RAF, also commonly employed by receptor tyrosine kinases (RTKs), thereby providing opportunities for signaling crosstalk. Several members of the TGF-β superfamily are being explored as potential targets to control drug resistance and metastatic spread, both important barriers to cure in HNSCC. In this chapter, the roles of TGF-β in HNSCC are described, with particular focus on molecular signaling, TGF-β’s role in controlling gene expression, and relevant therapeutic directions involving TGF-β.

Objective: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.Material and Methods: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.Results: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).Conclusion: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.

Objective: To evaluate the action of ascorbic acid on the healing of malnourished rats' cutaneous wounds compared with normal weight rats. Methods: We used 92 adult, male Wistar rats divided into four groups: 24 normal weight rats given only water and chow; 24 normal weight rats given vitamin C by gavage (340 mg/kg 12/12 hours); 22 malnourished rats given only water and chow; and 22 malnourished rats given vitamin C by gavage (340 mg/kg 12/12 hours). Malnutrition was induced by feeding the animals half of their daily energy requirement for 30 days. Two incisions were made, one sutured (healing by primary intention) and one left unsutured (healing by secondary intention). The rats were euthanized on the third, seventh, and fourteenth days of the experiment. Results: The following parameters differed significantly between the groups (p&gt;0.05): granulation of the wound edge in the primary and secondary intention; extent of injuries on day 7 for primary intention and on day 3 for secondary intention; reepithelialization on day 7 for primary intention; fibrin-leukocyte scab on day 14 for primary intention; amount of neovascularization and concentration of macrophages, fibroblasts, and collagen fibers for primary and secondary intention. Conclusion: The use of vitamin C in malnourished and normal weight rats increases fibroblast proliferation and collagen deposition in the tissue, which helps to improve healing both by primary and secondary intention.

Cardiac fibrosis, marked by excessive collagen accumulation and tissue remodelling, is a key factor in heart dysfunction across various cardiovascular conditions. With limited effective treatments currently available, there is growing interest in exploring natural therapies like green tea and green coffee for their potential antifibrotic properties. Both beverages contain bioactive compounds, such as catechins and caffeic acid, known for their antioxidant, anti-inflammatory, and cardioprotective effects. Green tea has been shown to reduce oxidative stress, lower fibrosis-related markers, and limit collagen deposition in heart tissue. Similarly, caffeic acid from coffee has demonstrated the ability to block fibrosis-driving pathways, such as TGF-β1 signalling, and support cardiac recovery following myocardial infarction. Moreover, the combined use of green tea and decaffeinated green coffee has been found to improve metabolic health by influencing cardiac insulin pathways, which could help mitigate fibrosis in metabolic syndrome models. This review consolidates recent evidence on the mechanisms and benefits of green tea and green coffee in addressing cardiac fibrosis. It highlights their potential as accessible, non-invasive treatment options and underscores the need for further studies to confirm their therapeutic applications in clinical settings.

Increased signaling by transforming growth factor beta (TGFbeta) has been implicated in systemic sclerosis (SSc; scleroderma), a complex disorder of connective tissues characterized by excessive accumulation of collagen and other extracellular matrix components in systemic organs. To directly assess the effect of sustained TGFbeta signaling in SSc, we established a novel mouse model in which the TGFbeta signaling pathway is activated in fibroblasts postnatally. The mice we used (termed TBR1(CA); Cre-ER mice) harbor both the DNA for an inducible constitutively active TGFbeta receptor I (TGFbetaRI) mutation, which has been targeted to the ROSA locus, and a Cre-ER transgene that is driven by a fibroblast-specific promoter. Administration of 4-hydroxytamoxifen 2 weeks after birth activates the expression of constitutively active TGFbetaRI. These mice recapitulated clinical, histologic, and biochemical features of human SSc, showing pronounced and generalized fibrosis of the dermis, thinner epidermis, loss of hair follicles, and fibrotic thickening of small blood vessel walls in the lung and kidney. Primary skin fibroblasts from these mice showed elevated expression of downstream TGFbeta targets, reproducing the hallmark biochemical phenotype of explanted SSc dermal fibroblasts. The mouse fibroblasts also showed elevated basal expression of the TGFbeta-regulated promoters plasminogen activator inhibitor 1 and 3TP, increased Smad2/3 phosphorylation, and enhanced myofibroblast differentiation. Constitutive activation of TGFbeta signaling in fibroblastic cells of mice after birth caused a marked fibrotic phenotype characteristic of SSc. These mice should be excellent models with which to test therapies aimed at correcting excessive TGFbeta signaling in human scleroderma.

Metastasis is the leading cause of cancer-related deaths. Transforming growth factor beta (TGF-β) signaling drives metastasis and is strongly enhanced during cancer progression. Yet, the use of on-target TGF-β signaling inhibitors in the treatment of cancer patients remains unsuccessful, highlighting a gap in the understanding of TGF-β biology that limits the establishment of efficient anti-metastatic therapies. Here, we show that TGF-β signaling hyperactivation in breast cancer cells is required for metastasis and relies on increased small extracellular vesicle (sEV) secretion. Demonstrating sEV’s unique role, TGF-β signaling levels induced by sEVs exceed the activity of matching concentrations of soluble ligand TGF-β. Further, genetic disruption of sEV secretion in highly-metastatic breast cancer cells impairs cancer cell aggressiveness by reducing TGF-β signaling to nearly-normal levels. Otherwise, TGF-β signaling activity in non-invasive breast cancer cells is inherently low, but can be amplified by sEVs, enabling invasion and metastasis of poorly-metastatic breast cancer cells. Underscoring the translational potential of inhibiting sEV trafficking in advanced breast cancers, treatment with dimethyl amiloride (DMA) decreases sEV secretion, TGF-β signaling activity, and breast cancer progression in vivo. Targeting both the sEV trafficking and TGF-β signaling by combining DMA and SB431542 at suboptimal doses potentiated this effect, normalizing the TGF-β signaling in primary tumors to potently reduce circulating tumor cells, metastasis, and tumor self-seeding. Collectively, this study establishes sEVs as critical elements in TGF-β biology, demonstrating the feasibility of inhibiting sEV trafficking as a new therapeutic approach to impair metastasis by normalizing TGF-β signaling levels in breast cancer cells.

Introduction: Keloid and hypertrophic scar are pathological scars resulting from excessive accumulation of collagen in wound healing process. Data about profiles of keloid and hypertrophic scar are rarely found in Indonesia. Therefore, it is necessary to conduct research related to keloid and hypertrophic scar. This study aimed to provide valuable data for further research.Methods: This was descriptive retrospective study evaluating 105 patients treated for keloid and hypertrophic scar from 2014 to 2017 using medical records of working-age patients.Results: Mostly in patients between 17-25 years old (40%). Comparison between male and female patients were 1.07:1 (keloid) and 1.09:1 (hypertrophic scar). As many as 10.71% of patients of keloid and 17.39% patients of hypertrophic scar were private employees. 23.21% patients with keloid and 23.91% patients of hypertrophic scar were Javanese. 14.29% patients of keloid and 19.57% patients of hypertrophic scar tend to have daily indoor activities. 17.86% patients of keloid and 26.09% patients of hypertrophic scar felt dark-skinned toned. Most keloid scars were caused by traumatic lesions (32.14%), located on the chest (19.54%), and treated by corticosteroid injection. Hypertrophic scar mostly caused by burn injury (54.35%), located on the face (29.55%), and treated by excision surgery.Conclusion: Both keloid and hypertrophic scars were mostly developed in 17-25 years old, male, private employees, Javanese ethnic, dark skin tone patients, with daily indoor activities, caused by traumatic lesion and located on the chest, earlobe, and hand, treated by corticosteroid injection (keloid). Meanwhile, hypertrophic scars are mostly caused by a burn injury on the face and treated by excision surgery.

Keloid is characterized by excessive collagen accumulation, but the mechanism of keloid formation remains unknown, and none of the treatment modalities are consistently effective. Heat shock protein (HSP) 47, known as a collagen-specific molecular chaperone, plays a critical role in collagen biosynthesis. Our previous research has demonstrated that HSP47 is highly expressed in keloid compared with normal skin tissues, which indicates that there might be a close relationship between overexpression of HSP47 and excessive collagen accumulation in keloid formation. To further investigate whether overexpression of HSP47 might promote excessive collagen deposition in keloid formation, we examined the alteration of intracellular and extracellular collagen expression, following inhibition of HSP47 expression in keloid fibroblast cells by the RNA interference technique. Three constructed psiRNA-hH1neo plasmids, carrying three pairs of related HSP47-shRNA (small hairpin RNA), respectively, were transfected into keloid fibroblast cells and compared with three control groups. After transfection, the mRNA and protein expression of HSP47 and collagen type I were detected by quantitative real-time polymerase chain reaction and Western blot; the content of extracellular secreting collagen was assessed by hydroxyproline assay; and the MTT [3-(4, 5-dimethylthiazolyl-2)-2, 5-diphenyltetrazolium bromide] method was adopted to examine the proliferation of keloid fibroblast cells. Both the mRNA and protein levels of HSP47 in keloid fibroblast cells decreased dramatically 48 h after post-transfection of three related HSP47-shRNA plasmids, compared with control groups. Following the downregulation of HSP47, we found that the expression of intracellular and extracellular collagen was correspondingly reduced. On the other hand, the MTT assay showed that transfection of HSP47-shRNA plasmids did not influence the growth of keloid fibroblast cells. Combined with our previous histological results, we propose that overexpression of HSP47 in keloid fibroblast cells could induce excessive collagen accumulation by enhancing synthesis and secretion of collagen, which not only presents a possible mechanism of keloid formation, but also offers a therapeutic potential of RNA interference to HSP47 for the treatment of keloid and other fibroproliferative disorders.