Search Results (132)

Micro- and nanoplastics (MNPs) are ubiquitous environmental pollutants recognized as emerging and relevant risk factors for numerous human diseases, including cardiovascular diseases. MNPs enter the human body through ingestion, inhalation, and dermal penetration, and their toxicity varies according to size, shape, and chemical composition, most notably between microplastics (>1 µm) and nanoplastics (<1 µm), which differ in cellular uptake mechanisms and biodistribution. Recent evidence has confirmed their presence in cardiac and vascular tissues, raising significant concerns about their potential impact on human health. This review summarizes current knowledge on MNP exposure sources, physicochemical properties, and systemic bioavailability, with a particular emphasis on the mechanisms of transport that facilitate their deposition within the myocardium and vasculature. It further addresses a broad spectrum of cardiotoxic effects, including oxidative stress, mitochondrial injury, immune activation, ion channel disruption, cell death, and fibrosis. Endothelial dysfunction, vascular injury, and pro-atherogenic activity are also discussed. In addition to outlining existing detection techniques and emerging in vitro models, the review highlights initial steps toward the development of preventive strategies. Concluding with key knowledge gaps and future research directions, this article underscores the urgent need for standardized measurement tools, deeper insights into damage mechanisms, and clinical interventions to prevent MNP-induced cardiovascular diseases. Full article

Mice lacking epidermal Pparg (Pparg-/-^epi) exhibit increased cutaneous carcinogenesis, while PPARγ signaling is reduced in actinic keratoses (AKs) and cutaneous squamous cell carcinomas (cSCCs). Using transcriptomic analysis, we now show that the top upregulated genes in Pparg-/-^epi mouse skin, human AKs and cSCCs encode multiple damage-associated molecular patterns (DAMPs) that are TLR4 ligands, while the TLR4 agonist lipopolysaccharide (LPS) is also predicted to be the top common activated upstream regulator in both Pparg-/-^epi mouse skin and in tumor datasets. By single-cell sequencing, DAMP expression was particularly elevated in myeloid cells and myofibroblasts of Pparg-/-^epi mice, and these cell types exhibit transcriptional changes consistent with TLR4 signaling. Myeloid cells also exhibited a loss of Pparg expression and activity. Transcriptional analysis of published LPS-treated macrophages also reveals a decrease in PPARγ activity. Fibroblasts from Pparg-/-^epi mice included cells with a gene expression profile resembling myofibroblasts found in cancer and fibrotic diseases. This was accompanied by increased dermal fibrosis in aged mice and a transcriptomic profile that indicates a key role for both TLR4 and TGFβ signaling. These data suggest that loss of epidermal PPARγ may disrupt counterbalancing PPARγ–TLR4 signals, leading to chronic inflammation and fibrosis, hallmarks of cutaneous neoplasia. Full article

Soft tissue reconstruction often requires biomaterials that provide temporary mechanical support while permitting vascular integration and tissue remodeling. In reconstructive breast surgery, these demands converge within a uniquely challenging environment characterized by large surface areas, variable perfusion, frequent exposure to radiation, and reliance on prosthetic implants. Consequently, breast reconstruction serves as a clinically relevant model for evaluating the performance and limitations of soft tissue scaffolds. Acellular dermal matrices (ADMs) were introduced to provide biologically derived reinforcement capable of host integration and neovascularization. Although ADM has transformed implant-based reconstruction, clinical experience has revealed important limitations, including variability in mechanical properties, inconsistent vascularization, susceptibility to fibrosis, and suboptimal performance in compromised tissue beds. These challenges have driven increasing interest in synthetic polymer scaffolds engineered for reproducible mechanics, controlled degradation, and scalable manufacturing. This narrative review examines the evolution from ADM to synthetic and hybrid scaffold systems in breast reconstruction. We discuss how scaffold architecture, thickness, porosity, and degradation kinetics influence angiogenesis, immune response, and mechanical load transfer during healing. Hybrid strategies that incorporate selective bioactivity within synthetic frameworks are also explored, highlighting their translational promise and current limitations. These principles are particularly relevant in implant-based breast reconstruction, where scaffold performance directly influences complication rates, implant stability, and long-term outcomes. Collectively, breast reconstruction serves as a rigorous translational model demonstrating that optimal soft tissue scaffolds must balance vascular permissiveness, mechanical reliability, and predictable resorption to optimize reconstructive success and guide future biomaterial innovation. Full article

Capsular contracture (CC) remains the most common long-term complication of implant-based breast reconstruction (IBBR), significantly impacting cosmetic outcomes, patient satisfaction, and reoperation rates. Despite substantial advances in surgical technique, implant technology, and perioperative management, the incidence of clinically significant contracture persists at approximately 3–5% at five years in non-irradiated patients and escalates dramatically—to 20–50%—in those receiving postmastectomy radiation therapy (PMRT). The etiology is multifactorial, involving subclinical biofilm formation, a dysregulated host immune and foreign-body response, and radiation-induced fibrosis. This narrative review synthesizes contemporary evidence on the pathophysiology, clinical assessment, and modifiable risk factors for CC in IBBR, with particular emphasis on implant surface characteristics (smooth, textured, and polyurethane[PU]-coated), placement plane (prepectoral versus subpectoral), the role of acellular dermal matrices (ADMs), reconstruction timing (direct-to-implant versus two-stage), and the complex interplay with radiotherapy—including radiation timing, fractionation, and emerging delivery techniques. We also address ongoing controversies, including the lack of standardized objective diagnostic criteria, the comparative effectiveness of ADM versus PU-coated implants, and the optimal sequencing of radiation relative to reconstruction. By integrating the latest evidence from very recent major meta-analyses and national registries, this review provides an updated synthesis. We further propose an evidence-based clinical decision framework for CC risk mitigation. This review aims to inform individualized surgical decision-making and identify priority areas for future investigation. Full article

Background: Cellulite is a highly prevalent aesthetic concern characterized by structural remodeling of subcutaneous adipose tissue and fibrous septa, resulting in visible skin irregularities. Despite the availability of many injectable treatments with documented efficacy, most standard approaches adopt uniform protocols that overlook interindividual anatomical variability, potentially limiting treatment precision and clinical outcomes. This retrospective case–control study evaluated the Modulated Insertion of Regenerative Activation (MIRA), a technique that individualizes needle length and injection angle according to ultrasound findings, modulating insertion parameters to stimulate regenerative responses within dermal and subcutaneous layers. Methods: Clinical and ultrasonographic data from 120 women with stage 3 cellulite were analyzed over a 30-day follow-up period. Stage 3A patients received carbon dioxide therapy (CDT), whereas stage 3B patients underwent injectable solution therapy (IST). Within each treatment, patients were allocated to MIRA or control groups. Results: Compared with controls, MIRA showed greater reductions in adipose tissue thickness (CDT: −1.6 mm; IST: −1.5 mm; p_adj = 0.002), nodules, pain, edema, and fibrosis, with improved fascia regularity. Patient satisfaction was higher in MIRA (CDT: 8.1 ± 1.6; IST: 8.5 ± 1.4; p_adj = 0.002), and over 76% reported improved skin quality. Conclusions: These explorative findings suggest that ultrasound-guided modulation of needle parameters with MIRA may enhance structural and esthetic outcomes compared with standard approaches. Prospective randomized trials are needed to confirm these results. Full article

Systemic sclerosis (SSc) is a multi-organ autoimmune disease characterized by fibrosis of the skin and internal organs. Interstitial lung disease (ILD) is a major complication and leading cause of mortality in SSc. Transforming growth factor-β (TGF-β) has been implicated as a central mediator of fibrosis; however, while TGF-β1 has been extensively studied, the roles of TGF-β2 and TGF-β3 remain incompletely defined. Here, we systematically compared the effects of TGF-β1, TGF-β2, and TGF-β3 in dermal and lung fibroblasts, evaluating extracellular matrix synthesis and contraction, cytokine secretion, proliferation, and myofibroblast differentiation. TGF-β2 and TGF-β3 induced greater profibrotic cytokine release of Interleukin (IL)-6 and IL-11 and increased collagen-I and fibronectin synthesis compared with TGF-β1 in dermal and lung fibroblasts (all p < 0.05). TGF-β2 and TGF-β3 stimulated greater collagen-I contraction in dermal fibroblasts (p < 0.05), but greater myofibroblast differentiation in lung fibroblasts (p < 0.05). The TGF-β isoforms did not affect proliferation. All TGF-β isoforms activated SMAD2/3 signalling; however, TGF-β2 and TGF-β3 reduced expression of TGF-β Receptor II and the inhibitory regulator, SMAD7. In summary, TGF-β2 and TGF-β3 have a more pronounced profibrotic effect than TGF-β1 on dermal and lung fibroblast functions, making them potential targets for treatment for skin and lung fibrosis in diseases such as SSc. Full article

Elevated levels of platelet-derived growth factor (PDGF) isoforms in fibrosis are implicated in driving a dysfunctional profibrotic fibroblast phenotype. This study investigated the differential effects of the five PDGF isoforms (AA, AB, BB, CC, and DD) in inducing neonatal dermal and fetal lung fibroblast contraction, proliferation, cytokine production, myofibroblast differentiation, and extracellular matrix (ECM) deposition. All PDGF isoforms, except PDGF-AA, increased contraction of 3-dimensional collagen I gels by dermal (p < 0.01) and lung fibroblasts (p < 0.05) compared to media control. PDGF-AB, BB, and CC enhanced proliferation only in dermal fibroblasts (p < 0.05). PDGF-BB induced profibrotic IL-11 cytokine release in dermal and lung fibroblasts (p < 0.0001) and IL-6 cytokine release in dermal fibroblasts (p < 0.05) compared to media control. None of the PDGF isoforms affected ECM synthesis or myofibroblast differentiation. Dermal fibroblasts exhibited elevated PDGF Receptor-β (PDGFRβ) expression (p < 0.01) and increased basal ERK1/2 phosphorylation (p < 0.05) compared to lung fibroblasts. In summary, PDGF modulates fibroblast functions in a tissue-specific manner, with PDGF-BB driving profibrotic processes in dermal fibroblasts through high PDGFRβ expression and ERK1/2 signalling. Further research is needed to explore the benefit of tissue and isoform-specific PDGF inhibition strategies in skin and lung fibrosis. Full article

Cutaneous fibrosis is characterized by aberrant wound healing with excessive extracellular matrix deposition, sustained inflammation, and oxidative stress, while currently available therapies show limited efficacy and safety. A Dual Hyaluronic Acid Compound (DHC), consisting of high-molecular-weight, low-molecular-weight, and minimally cross-linked hyaluronic acid, has demonstrated regenerative and antioxidant properties, but its anti-fibrotic effects have not been fully explored. This study investigated the anti-fibrotic potential of DHC using a bleomycin-induced murine dermal fibrosis model and a UVB-irradiated ex vivo human skin model. In C57BL/6 mice, dermal fibrosis was induced by daily bleomycin injections for three weeks, followed by intradermal DHC administration. Histological and biomechanical analyses showed that DHC significantly reduced dermal thickness, collagen deposition, and skin hardness compared with untreated fibrotic controls. DHC decreased α-SMA expression and increased MMP1 levels, indicating attenuation of myofibroblast activation and enhanced matrix remodeling. It also reduced macrophage markers (CD68, CD163) and pro-inflammatory cytokines (IL-1β, TNF-α). Furthermore, DHC restored superoxide dismutase (SOD) and catalase (CAT) activity and upregulated NRF2, HO-1, and NQO1 expression in the in vivo model. Similarly, DHC upregulated SOD and CAT activity and reduced pro-inflammatory cytokines (IL-6, TNF-α) in the ex vivo human skin model. These findings suggest that DHC exerts multimodal anti-fibrotic effects through coordinated regulation of fibroblast activation, inflammation, and oxidative stress, supporting its potential as a therapeutic approach for cutaneous fibrosis. Full article

Skin fibrosis is characterized by excessive extracellular matrix (ECM) deposition, leading to tissue dysfunction and scarring. Transforming growth factor (TGF)-β is a central mediator of fibrosis. We previously identified CD109 as a TGF-β co-receptor and negative regulator of TGF-β signaling and fibrotic responses and showed that its epidermal overexpression reduces dermal fibrosis in vivo. However, the effects of CD109 loss in the dermis remain unclear. The current study investigates the impact of CD109 knockout (KO) on skin fibrosis using a bleomycin-induced fibrosis mouse model. Following bleomycin treatment, CD109 KO mice showed increased collagen I deposition and elevated fibronectin, CCN2, and α–smooth muscle actin expression in the skin, indicating enhanced ECM production and myofibroblast differentiation compared with wild-type mice. Additionally, CD109 KO mice displayed enhanced Smad1 and Smad2/3 phosphorylation in the skin, indicating heightened TGF-β signaling. In vitro, CD109 KO fibroblasts exhibited increased TGF-β-induced migration and collagen contraction. These findings suggest that CD109 deficiency exacerbates dermal fibrosis by promoting TGF-β/Smad signaling and myofibroblast activation. Given its dysregulation in fibrotic disorders such as scleroderma, our results identify CD109 as a key regulator of skin homeostasis by modulating ECM production and fibroblast activation, underscoring its potential as a therapeutic target in fibrotic disorders. Full article

Chromoblastomycosis is a chronic mycosis of the skin and subcutaneous tissue typically caused by traumatic inoculation of dematiaceous fungi of the Herpotrichiellaceae. A 59-year-old male presented with a 12-month history of an asymmetrical, scaly plaque on the left forearm that has been slowly increasing in size. Past medical history included atrial fibrillation on apixaban, hypertension and a cardiac stent. A 4 mm punch biopsy of the left forearm revealed superficial dermal fibrosis with mild pseudoepitheliomatous hyperplasia and granulomatous inflammation with scattered multinucleate histiocytes. There were giant cells with dark brown, somewhat round, yeast-like structures, some with internal septation exhibiting moderate staining for PAS, compatible with Medlar bodies suggestive of chromoblastomycosis. The patient was on rosuvastatin, rendering itraconazole not a possible treatment option, and instead the patient underwent curettage and cautery with two bouts of cryotherapy freeze and thaw cycles. A twelve-month follow-up noted a crusted area on the distal aspect of the scar. A shave biopsy of this area revealed pigmented organisms suggesting a recurrence of chromoblastomycosis. A further excisional biopsy was performed, with no evidence of chromoblastomycosis. This case highlights multiple surgical options for the management of chromoblastomycosis in patients where medical management is contraindicated. It highlights the therapeutic challenge of this disease due to frequent recurrence of lesions and that repeat biopsy may be efficacious in monitoring for recurrence. Full article

Responses to cutaneous injury differ fundamentally across developmental stages in several mammal species. During early human gestation, when the fetus is less than 24 weeks old, wounds are capable of restoring normal tissue architecture without forming fibrotic scars. In contrast, postnatal and adult injuries typically resolve through the process of fibrosis. This divergence reflects coordinated differences in epidermal and dermal compartments, inflammatory signaling, extracellular matrix (ECM) composition, mechanical cues, and gene regulation. Recent studies have demonstrated that dermal fibroblasts are no longer considered a uniform population but instead arise from distinct developmental lineages with stable functional identities. Engrailed-1-negative fibroblasts (ENFs) predominate in early fetal skin in mice and support regenerative repair, while Engrailed-1-positive fibroblasts (EPFs) emerge later in development and are the principal contributors to fibrotic matrix deposition following injury. The developmental shift between these fibroblast populations coincides with the loss of scar-free healing capacity. This review examines the current understanding of fibroblast lineage specification, with particular emphasis on the roles of mechanotransduction, extracellular matrix cues, and epigenetic regulation. Elucidating how these lineage-encoded programs are established and maintained may enable strategies to reprogram adult fibroblasts toward a fetal-like regenerative state and thereby promote scar-free tissue repair. Full article

Background/Objectives: UVB radiation triggers oxidative stress, inflammation and extracellular matrix (ECM) remodeling in dermal fibroblasts, contributing to skin aging and fibrosis. Plant-derived extracts with antioxidant and anti-inflammatory activity may counteract these effects. This study evaluated the protective role of Damor Triticum vulgare Aqueous Extract (DTVE) in human dermal fibroblasts (HDFs) exposed to UVB. Methods: Primary HDFs were irradiated with UVB (1.50 J/m²) and treated with DTVE either after irradiation (post-ir) or before and after irradiation (pre-ir). Cell viability was assessed by Trypan Blue and MTT assays. Inflammatory cytokines, fibrosis-related genes, p21 expression, mitochondrial ROS (MitoSOX) and αSMA accumulation were quantified by qRT-PCR, ELISA and immunofluorescence. Results: DTVE was not cytotoxic and preserved HDF viability under UVB exposure. UVB significantly increased pro-inflammatory cytokines, profibrotic markers, αSMA, mitochondrial ROS and p21. DTVE reduced all these UVB-induced alterations, with the pre-ir regimen providing the strongest protection. The extract attenuated early inflammatory activation, limited fibroblast-to-myofibroblast transition and decreased mitochondrial oxidative stress while reducing p21 upregulation. Conclusions: DTVE exerts protective antioxidant, anti-inflammatory and antifibrotic effects in UVB-exposed fibroblasts, particularly when used as pretreatment. These findings support DTVE as a promising candidate to mitigate UVB-induced dermal damage and warrant further investigation for potential therapeutic and cosmetic applications. Full article

Uncontrolled fibrosis via excess deposition of extracellular matrix (ECM) is a hallmark of hypertrophic scars and keloids. A decellularized ECM biomaterial from porcine small intestinal submucosa (SIS; Biodesign or BioD, Cook Biotech, Inc.) is widely used in clinical applications for tissue repair. The objective of the current study was to test the effects of BioD scaffolds, as compared with collagen constructs, on normal human skin (nFB) and keloid fibroblasts (kFBs). Immortalized human dermal fibroblasts (hFBs) and human keloid fibroblasts (hKFs) were utilized for all experiments. Cells were cultured either on BioD membranes or on collagen gel (used as a control). To investigate pro-fibrotic signaling pathways, real-time quantitative PCR (qPCR), ELISA, and gene knockdown studies were conducted on cultured cells. ECM gene expression array revealed that BioD significantly attenuated (p < 0.05) the expression of thrombospondin-1 and fibronectin-1, two drivers of fibrosis in nFB as well as kFB. BioD-repressed thrombospondin-1 and fibronectin-1 gene expression manifested as significant downregulation (n = 5–6; p < 0.05) of both proteins in nFB and kFB. The levels of latent transforming-growth factor (LAP-TGFβ-1) were markedly reduced (n = 5; p < 0.05) in both nFB and kFB cultured on BioD, but not the other constructs. Knockdown of FN1 using siRNA significantly attenuated (n = 5, p < 0.05) pro-fibrotic responses, including expression of Col1A1 and the levels of LAP-TGFβ-1 in nFB, suggesting that downregulation of FN1 by BioD is one of the primary underlying mechanisms of attenuated pro-fibrotic responses in keloid fibroblasts. This study reports that a decellularized ECM scaffold may significantly attenuate pro-fibrotic responses in both normal and keloid fibroblasts via TSP1 and FN1-dependent mechanisms. Full article

Background/Objectives: Duchenne muscular dystrophy (DMD) is characterized by progressive skeletal and cardiac muscle degeneration driven by inflammation and fibrosis, ultimately leading to cardiomyopathy and premature death. Deramiocel, an allogeneic cell therapy composed of cardiosphere-derived cells (CDCs), has demonstrated potent anti-fibrotic and immunomodulatory effects in preclinical models and clinical trials, including HOPE-2 and its open-label extension (HOPE-2 OLE), where Deramiocel treatment significantly attenuated progression of skeletal and cardiac muscle dysfunction. Methods: CDCs in Deramiocel were cultured to generate CM enriched with secreted exosomes and factors, which was subsequently applied to primary human dermal fibroblasts (HDFs). Following co-culture, ex-pression of collagen type I alpha 1 (COL1A) and collagen type III alpha 1 (COL3A) was measured by qRT-PCR. Non-conditioned media serves as a control in the assay. Reduction in COL1A and COL3A expression therefore provides a direct and clinically relevant measure of the anti-fibrotic activity of Deramiocel. Results: A novel in vitro potency assay was developed to quantify the anti-fibrotic activity of Deramiocel. Conditioned media (CM) from over one hundred Deramiocel manufacturing lots significantly suppressed expression of collagen type I alpha 1 (COL1A) and collagen type III alpha 1 (COL3A) in primary human dermal fibroblasts compared with non-conditioned media controls, establishing a robust, reproducible readout of anti-fibrotic activity. The effect was dose-dependent and abrogated by sequential depletion of exosomes and soluble proteins, implicating both as critical mediators of Deramiocel’s mechanism of action. Importantly, CDCs in Deramiocel lots classified as potent by this assay were shown to exert a clinically meaningful benefit in DMD patients in the HOPE-2 and HOPE-2 OLE studies. Conclusions: This assay represents a mechanistically informative, therapeutically relevant, reproducible, scalable, and regulatory-compliant approach for assessing Deramiocel potency, enabling consistent manufacturing, and facilitating the continued development of Deramiocel as a disease-modifying therapy for DMD. 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