Search Results (547)

Sixteen polyketides, including six new compounds (1–2, and 5–8), were isolated from the culture of the marine sponge-associated fungus Neopestalotiopsis sp. SCSIO 41422. Their structures were elucidated through NMR, MS spectroscopic analyses, calculated electronic circular dichroism, quantum chemical NMR calculations, and X-ray single-crystal diffraction. To screen and evaluate the inhibitory activity of these polyketides in renal fibrosis, a TGF-β1-stimulated HK-2 cell model was used. All tested compounds (1, 5–8, and 11–12) at 10 µM showed obvious anti-fibrotic activity by inhibiting TGF-β1-induced α-SMA expression and extracellular matrix production (collagen I and fibronectin). Among them, gamahorin A (1) was shown to be the most potent and the most promising inhibitor against renal fibrosis. Full article

This paper investigates the ability of our selective small molecule TG2 inhibitor 1-155 in reducing fibrosis in a bleomycin-induced pulmonary fibrosis mouse model. Formulated as a fine stable suspension, 1-155 was delivered intranasally (IN) at 3 mg/kg via IN delivery once daily. It significantly inhibited collagen deposition in the lungs in the bleomycin-challenged mice. Compared to its vehicle control treatment, a significant reduction in a key myofibroblast marker α smooth muscle actin and TG2 was also detected in the 1-155-treated animals. Most importantly, 1-155 treatment significantly improved several key lung function parameters, such as cord compliance, vital capacity, and dynamic compliance, which are comparable to that found for the positive control nintedanib at a much higher dosage of 60 mg/kg twice daily via oral delivery. The 1-155-treated mice showed a trend in improvement of average body weight. For the first time, our study demonstrates the effectiveness of a selective small molecule TG2 inhibitor in reducing pulmonary fibrosis in a pre-clinical model. Importantly, we were able to correlate this effect of 1-155 with the improvement of animal lung function showing the potential of the use of TG2 inhibitors as a therapeutic treatment for fibrotic lung conditions like IPF. Full article

This study evaluated the effects of α2-adrenergic agonist, prostaglandin F2α analog, and EP2 receptor agonist on tunicamycin-induced endoplasmic reticulum (ER) stress and fibrosis in human trabecular meshwork (TM) cells. Human TM cells were treated with tunicamycin for 24 h, followed by cotreatment with brimonidine (BRI), latanoprost (LAT), or omidenepag (OMD). Immunocytochemistry was used to assess expressions of collagen type I alpha 1 chain (COL1A1), fibronectin, F-actin, and alpha-smooth muscle actin (α-SMA). Western blotting was performed to evaluate levels of C/EBP homologous protein (CHOP), 78-kDa glucose-regulated protein (GRP78), and splicing X-box binding protein-1 (sXBP-1). Real-time qPCR was used to examine the mRNA expressions of COL1A1, connective tissue growth factor (CTGF), fibronectin, α-SMA, CHOP, GRP78, and sXBP-1. Expressions of COL1A1, CTGF, F-actin, fibronectin, α-SMA, CHOP, GRP78, and sXBP-1 significantly increased after tunicamycin treatment. BRI cotreatment significantly downregulated the mRNA and protein expressions of GRP78, and LAT or OMD cotreatment significantly reduced the CHOP and sXBP-1 expressions compared to the tunicamycin-treated group. BRI, LAT, or OMD cotreatment significantly attenuated cellular cytoskeletal changes and the increase of fibrosis markers such as COL1A1, CTGF, fibronectin, and α-SMA. In addition, COL1A1 mRNA expression was significantly lowered with LAT or OMD cotreatment compared to the BRI-cotreated group. Cotreatment with α2-adrenergic agonist, prostaglandin F2α analog, or EP2 receptor agonist alleviates tunicamycin-induced ER stress in human TM cells. Full article

During corneal wound healing, transforming growth factor-beta 1 (TGF-β1) causes differentiation of quiescent keratocytes into myofibroblasts. Decorin has been investigated as a promising anti-fibrotic therapeutic for corneal healing due to its interaction with TGF-β1, collagen, and cell surface receptors. In this study, a novel microfluidic method for coating aligned collagen fibrils with decorin was developed to mimic the presence of decorin within the corneal stroma. Decorin was found to bind selectively to collagen and remained bound for at least five days. To investigate the effects of decorin coatings on keratocyte activation, primary rabbit keratocytes were cultured in the presence of TGF-β1 for 5 days on substrates with or without decorin and stained for α-smooth muscle actin (α-SMA). The expression of α-SMA was reduced by similar amounts on monomeric collagen (40%), random collagen fibrils (32%), and aligned collagen fibrils (32%) coated with decorin as controls. However, α-SMA expression was differentially expressed between the collagen substrates not coated with decorin, with significantly lower expression on uncoated aligned collagen fibrils compared to uncoated collagen monomers. Addition of decorin directly to culture media, had a limited effect on reducing myofibroblast differentiation. Taken together, these results demonstrate the importance of topography and ECM composition on keratocyte activation. Full article

Chronic liver diseases (CLDs) in dogs are progressive conditions that often lead to liver failure. Metabolic dysfunctions such as cholestasis, obesity, hyperlipidemia, and endocrine disorders play a key role in human liver diseases like MASLD (Metabolic Dysfunction Associated Steatotic Liver Disease) and MASH (Metabolic Dysfunction Associated Steatohepatitis), but their significance in canine CLDs is poorly understood. This study aims to evaluate the association between hepatic lipid accumulation and inflammation or fibrosis in canine CLDs and its potential association with metabolic dysfunctions. Sixteen client-owned dogs with CLDs were assessed for clinical data, histological features, and liver immunohistochemistry (IHC). Histological and IHC markers of inflammation (Iba-1, iNOS, NF-κB), fibrosis (CD206, α-SMA, Sirius Red), and lipid accumulation (adipophilin) were assessed to identify correlations with clinical conditions. The applied markers showed effectiveness in their use on canine liver tissue. Adipophilin-marked lipid accumulation correlated positively with inflammatory markers, indicating a link between steatosis and inflammation. Metabolic dysfunctions were linked to hepatic lipid accumulation and inflammation. These findings show a potential alignment of canine CLDs with human MASLD/MASH, where lipid-induced inflammation drives disease progression. IHC markers could effectively assess these processes, suggesting potential for guiding diagnostics and therapies, though further research is needed to clarify clinical associations. Full article

The epiligament (EL), described in 1990 as a connective tissue layer distinguishable from the ligament proper, has only recently gained recognition for its critical role in ligament function and repair. Previously overlooked, the EL is now understood to be a dynamic structure, particularly in the context of medial collateral ligament (MCL) healing. Rat model studies demonstrate that the EL actively contributes to ligament repair by serving as a source of cells and blood vessels, findings later corroborated in human studies. The EL’s role in spontaneous MCL healing highlights its importance, raising the question of whether differences in EL morphology and activity contribute to the poor healing capacity of the anterior cruciate ligament (ACL). Comparative studies reveal significant disparities in EL cellularity and activity between the ACL and MCL. The EL of the MCL is hypercellular, with robust expression markers like α-smooth muscle actin (α-SMA) and collagen types III and V, essential for tissue remodeling and structural integrity. Conversely, the ACL’s EL is less vascularized and exhibits weaker expression of these markers. While vascular endothelial growth factor (VEGF) promotes angiogenesis, its effectiveness is limited in the ACL due to restricted vascularization. Similarly, CD34, a progenitor cell marker, is more prominently expressed in the MCL’s EL, further supporting its superior healing potential. These findings suggest that the EL’s distinct structural and functional attributes are key determinants of ligament healing. Targeting the EL’s regenerative properties offers a promising therapeutic strategy, particularly for improving ACL repair outcomes. Further research is necessary to validate and expand these findings. Full article

Background and Aim: Biliary atresia is a rare, progressive disease that affects the bile ducts in newborns. Persistent bile duct obstruction induces various pathological conditions, including jaundice, inflammation, and liver fibrosis; however, the exact pathogenesis of biliary atresia is not yet fully understood. Nuclear factor-κB (NF-κB) is widely acknowledged as a key regulator in the pathogenesis of hepatitis and liver fibrosis, and extensive research has been conducted to develop strategies to effectively inhibit its activity to mitigate liver damage. Exosome-based therapeutic platforms offer targeted NF-κB inhibition with low immunogenicity and enhanced liver-specific delivery. This study aimed to evaluate the therapeutic efficacy of Exo-SrIκB in treating cholestatic liver fibrosis using experimental animal models. Methods: Exo-SrIκB (an exosome-based therapy containing the super-repressor IκB protein) using EXPLOR technology (Exosome engineering for Protein Loading via Optically Reversible protein-protein interactions) to encapsulate the super repressor IκB (SrIκB) within exosomes. The therapeutic efficacy of Exo-SrIκB was assessed in minipig and mouse models with experimentally induced cholestatic liver disease. Results: Administration of Exo-SrIκB significantly attenuated liver fibrosis progression in both animal models by inhibiting NF-κB nuclear translocation and reducing the expression of fibrotic markers. Treated animals exhibited reduced collagen deposition, lower α-SMA levels, and improved hepatic function compared to untreated controls. Conclusion: Exo-SrIκB effectively suppressed NF-κB signaling and alleviated liver fibrosis in experimental cholestatic liver disease models, suggesting that exosome-based therapeutics may offer a targeted and biocompatible application to managing liver fibrosis and other chronic liver diseases. Full article

Doxycycline (Dxy), a broad-spectrum antibiotic with anti-inflammatory effects, is commonly used in ophthalmology but is unstable as a topical eyedrop, degrading quickly into inactive forms and requiring frequent application. To address this, gelatin nanoparticles (GNPs) loaded with Dxy (DNPs) were developed as a stable ophthalmic nanomedicine for enhancing corneal wound healing by inhibiting matrix metalloproteinases (MMPs). In this study, female Sprague–Dawley rats underwent lamellar keratectomy, and various Dxy formulations—oral, conventional eyedrops, and DNP-containing eyedrops—were evaluated for corneal wound repair. Clinical assessments included fluorescein staining, slit-lamp biomicroscopy, spectral-domain optical coherence tomography (SD-OCT) imaging, histopathology, and immunohistochemistry for MMP-2, MMP-9, and α-SMA. The DNP group (0.01% Dxy in DNPs, applied twice daily) demonstrated faster corneal thickness recovery and epithelial healing on days 7 and 14 compared to 0.1% Dxy eyedrop treatments applied twice or four times daily. DNP-treated eyes also showed reduced angiogenesis intensity and lower MMP-2 and MMP-9 immunoreactive scores, with enhanced stromal recovery and reduced neovascularization. These results highlight DNPs’ potential as a superior treatment for corneal wounds, providing effective healing with less frequent dosing and lower drug concentrations. This study supports DNPs’ potential for clinical application as a stable and efficient therapeutic agent in ophthalmology. Full article

Effective bladder reconstruction remains a significant challenge in urology, particularly for conditions requiring partial or complete bladder replacement. In this study, the efficacy is evaluated of two types of scaffolds, silk fibroin (SF) and adipose-derived stem cells (ADSCs-SF), in promoting bladder regeneration and their associated outcomes. A rat model was used to compare the surgical outcomes and morphological recovery of bladder tissues implanted with SF and ADSCs-SF scaffolds. Post-operative recovery, including voiding ability and complication rates, was assessed. The morphological and histological changes of the regenerated bladder tissue were evaluated at multiple time points (2, 4, 8, and 12 weeks) using gross tissue analysis, histometric assessments, and immunohistochemical staining. Both scaffold types demonstrated successful integration into the bladder wall with no significant differences in body weight or voiding issues. The SF scaffold group exhibited graft shrinkage and a 41.6% incidence of bladder calculus formation. In contrast, the ADSCs-SF scaffold facilitated superior morphological restoration, with bladder tissue progressively adopting a more normal shape and no incidence of bladder calculus. Histological analysis revealed that the ADSCs-SF scaffold significantly promoted the regeneration of a more organized urothelium layer and smooth muscle tissue. It also resulted in higher vessel density and reduced infiltration of inflammatory cells when compared to the SF scaffold alone. Additionally, the ADSCs-SF group exhibited enhanced expression of key markers, including uroplakin III, a urothelial marker, and α-SMA, a smooth muscle cell marker. These findings suggest that the ADSCs-SF scaffold not only supports the structural integrity of the bladder but also improves tissue regeneration and reduces adverse inflammatory responses, offering a promising approach for bladder repair and reconstruction. Full article

Gastric cancer remains a malignancy with high incidence, mortality rates, and poor prognosis globally. Osteoclastogenesis-associated transmembrane protein 1 (OSTM1), a transmembrane protein overexpressed in various tumors, has unclear functions in gastric-cancer progression. This study explores OSTM1’s role in gastric-cancer proliferation and metastasis. OSTM1 expression was analyzed in gastric-cancer and adjacent tissues using immunohistochemistry and RT-qPCR. OSTM1 overexpression and knockdown cell lines were established to assess its effects on cancer-cell behavior through in vitro and in vivo experiments. Western blot and RT-qPCR were used to examine OSTM1’s regulation of S100A4 expression. OSTM1 was significantly overexpressed in gastric-cancer tissues, negatively correlating with TNM staging and overall survival. OSTM1 overexpression enhanced cancer-cell proliferation, colony formation, migration, and invasion, while its knockdown showed opposite effects. In vivo studies confirmed increased lung metastatic capability in high OSTM1-expressing cells. Mechanistically, OSTM1 positively regulated S100A4 expression, with S100A4 knockdown reducing OSTM1-enhanced metastasis. Gastric-cancer lung metastases showed higher microvascular density and α-SMA-positive fibroblast infiltration in the OSTM1 high-expression group. OSTM1 promotes gastric-cancer progression by upregulating S100A4 and modifying the tumor microenvironment through enhanced angiogenesis and fibroblast activation. OSTM1 represents a potential diagnostic and prognostic biomarker, with the OSTM1–S100A4 axis offering new therapeutic possibilities for gastric-cancer treatment. Full article

Fibronectin glomerulopathy (FG) is caused by fibronectin 1 (FN1) gene mutations. A renal biopsy was performed on a 4-year-old girl with incidentally discovered proteinuria (150 mg/dL); her family history of renal disease was negative. Markedly enlarged glomeruli (mean glomerular diameter: 196 μm; age-matched controls: 140 μm), α-SMA-positive and Ki-67-positive mesangial cell proliferation (glomerular proliferation index 1.76), the mild expansion of mesangial areas, no immune or electron-dense deposits, normal glomerular basement membrane, and diffusely effaced foot processes were observed. Genetic testing identified a de novo heterozygous mutation (Gly417Val) in the collagen-binding site of the FN II-2 domain, prompting fibronectin immunostaining. Strong mesangial positivity was noted, hence FG was diagnosed. The follow-up period of 29 months revealed nephrotic range proteinuria, intermittent microhematuria, glomerular hyperfiltration, and preserved renal function. The biopsy features of early childhood-onset FG were compared to a case of FG with a lobular pattern diagnosed in a 44-year-old patient with undulating proteinuria, microhematuria, hypertension known for a year, and a positive family history. Early childhood-onset FG was characterized by glomerular enlargement, mesangial proliferation, and no changes that suggested fibronectin deposition disease. In summary, the novel aspects of the case were that the mutation was located at the collagen-binding site of the FN1 gene, not identified earlier, and the histologic spectrum of FG was expanded by the observed mesangial proliferative pattern and striking glomerulomegaly. Now, FG should also be considered among the monogenic causes of proteinuric kidney diseases in pediatric nephrology practice. Full article

Background: Cholesterol gallstone disease (CGS) is often accompanied by gallbladder contraction dysfunction and chronic inflammation, but effective therapeutic options remain limited. This study investigates whether a low-intensity pulsed ultrasound (LIPUS) treatment can improve gallbladder motility and alleviate chronic inflammation while exploring the underlying mechanisms. Methods: Gallbladder motility was assessed through in vitro and in vivo contraction tests, while bile condition was evaluated by observing bile crystal clearance. Tissue analysis and Western blotting were performed to examine the expression of the cholecystokinin A receptor (CCKAR) and α-smooth muscle actin (α-SMA) as markers of gallbladder smooth muscle health and the inflammatory microenvironment. Blood cholesterol levels were measured via biochemical assays. Results: LIPUS treatment obviously enhanced gallbladder contractility in response to CCK-8 stimulation and accelerated bile crystal clearance. It also reduced inflammatory cell infiltration and tissue edema, and promoted new capillary formation in the gallbladder, mitigating the progression of CGS. Furthermore, LIPUS restored CCKAR expression and improved the thickness of the gallbladder smooth muscle layer, providing a structural basis for increased smooth muscle contractility. Conclusion: LIPUS improves gallbladder motility and reduces chronic inflammation in CGS by enhancing CCKAR expression and smooth muscle integrity. These findings highlight the potential of LIPUS as a non-invasive therapeutic approach for managing CGS. Full article

Bilio-biliary anastomosis (BBA) is a critical surgical procedure that is performed with the objective of restoring bile duct continuity. This procedure is often required in cases where there has been an injury to the extrahepatic bile ducts or during liver transplantation. Despite advances in surgical techniques, the healing of BBA remains a significant challenge, with complications such as stricture formation and leakage affecting patient outcomes. The stromal vascular fraction (SVF), a heterogeneous cell population derived from adipose tissue, has demonstrated promise in regenerative medicine due to its rich content of stem cells, endothelial progenitor cells, and growth factors. The objective of this study was to evaluate the potential of locally administered autologous SVF to enhance the healing of BBAs. Bilio-biliary anastomosis was performed on a swine model (female Landrace pigs). Six swine were divided into two groups: the treatment group (n = 3) received a local application of autologous SVF around the anastomosis site immediately following BBA formation, while the control group (n = 3) received saline. The primary outcomes were assessed over an eight-week period post-surgery, and included anastomosis healing, stricture formation, and bile leakage. Histological analysis was performed to evaluate fibrosis, angiogenesis, and inflammation. Immunohistochemistry was conducted to assess healing-related markers (CD34, α-SMA) and the immunological microenvironment (CD3, CD10, tryptase). The SVF-treated group exhibited significantly enhanced healing of the BBA. Histological examination revealed increased angiogenesis and reduced fibrosis in the SVF group. Immunohistochemical staining demonstrated higher vascular density in the anastomosed area of the SVF-treated group (390 vs. 210 vessels per 1 mm², p = 0.0027), as well as a decrease in wall thickness (1.9 vs. 1.0 mm, p = 0.0014). There were no statistically significant differences in mast cell presence (p = 0.40). Immunohistochemical staining confirmed the overexpression of markers associated with tissue repair. Local injections of autologous SVF at the site of BBA have been demonstrated to significantly enhance healing and promote tissue regeneration. These findings suggest that SVF could be a valuable adjunctive therapy in BBA surgery, potentially improving surgical outcomes. However, further investigation is needed to explore the clinical applicability and long-term benefits of this novel approach in clinical practice as a minimally manipulated cell application. Full article

One new gliotoxin derivative fumianthrogliotoxin (1), one new indoquizoline alkaloid N3-(methyl propionate) indoquizoline (2), and three novel indole alkaloids, anthroxyindole (3), (±)-asperfumiindole A (4), and (±)-asperfumiindole B (5), together with 16 known compounds (6–21), were isolated from the culture of deep-sea derived fungus Aspergillus fumigatus AF1. Their chemical structures and absolute configurations were determined through the analysis of NMR data in combination with electronic circular dichroism (ECD) calculations and other spectroscopic analyses. Compounds 2–11 and 13–21 were evaluated for anti-pulmonary fibrosis activity. Compounds 8 and 13 displayed significant downregulation of the mRNA expression levels of all three molecular markers (COL1A1, α-SMA and FN1), with compound 13 exhibiting the best performance among all the tested compounds. Full article

Background: Leiomyoma (LM) is the most commonly identified tumor in the genital tract, occurring in 70–80% of women. The only treatment option is surgery, which significantly influences healthcare costs and negatively influences women’s survival and reproductive capacity. Therefore, identifying safe and effective chemopreventive and treatment modalities is needed. Methods: We investigated the effects of 12 months of daily curcumin (0, 25.8, and 53 mg/kg) diet on the incidence and growth of spontaneously developing LM tumors in a galline (hen) model. Results: LM tumors were detected in 58.9% (53/90) of the control hens as spontaneous occurrences, while they were observed in 37.7% (34/90) and 24.5% (22/90) of hens treated with daily doses of 25.8 mg or 53.0 mg, respectively, over 12 months. This reduced LM development by 35% and 58.5%, respectively (p = 0.004). We also observed a dose-dependent inhibition of LM-tumor growth and NF-κB, mTOR, p70S6K1, and 4E-BP1 signaling while inducing Nrf2/HO1 pathway induction LM tumors collected from hens fed with curcumin (p < 0.05). Curcumin intake notably reduced levels of TGF-β1, α-SMA, and collagen type 1, with dose-dependent effects (p < 0.001). Conclusions: The findings suggest that daily curcumin consumption significantly reduces the incidence of naturally occurring LMs and suppresses tumor growth. This indicates that regular curcumin intake may be an effective preventive measure against LMs. Full article