Search Results (103)

Background: Idiopathic pulmonary fibrosis (IPF) is closely associated with fibroblast proliferation, macrophage polarization, and the accumulation of extracellular matrix (ECM). Targeting CSF-1R can rebalance macrophages, reduce ECM deposition, and block pro-fibrotic signaling. Methods: A Fab fragment targeting CSF-1R was screened via phage display. After sequence optimization, it was constructed into an IgG1 antibody (BC006). In vitro activity, domain binding, and signaling blockade were investigated, and in vitro safety indicators were evaluated. Efficacy was assessed using an induced IPF organoid-on-a-chip and bleomycin-induced mouse model. In vivo safety evaluation was conducted in cynomolgus monkeys. Results: BC006 showed an EC₅₀ value of 226 ± 57 nM and a KD of 30 ± 2 nM. It specifically bound to the Ig4-5 domain of CSF-1R by inhibiting receptor dimerization without blocking ligand binding. It could dose-dependently inhibit the differentiation of monocytes into M2 macrophages and exert anti-IPF effects. In the induced IPF organoid-on-a-chip model, BC006 maintained lung barrier function and decreased α-SMA and Collagen I. It also improved lung function and attenuated the degree of fibrosis in the mouse model. Moreover, BC006 had no ADCC, CDC, cytokine release, or hemagglutination, and demonstrated favorable safety profiles in cynomolgus monkeys. Conclusions: BC006 is a novel anti-fibrosis antibody specifically targeting the CSF-1R Ig4-5 domain and offers a new therapeutic strategy for IPF. Full article

Diabetic nephropathy (DN) is a major microvascular complication of diabetes mellitus, and a leading cause of chronic kidney disease (CKD) and end-stage renal disease (ESRD) worldwide. It is characterized by proteinuria, mesangial expansion, glomerulosclerosis and progressive loss of renal function. Current therapeutic strategies of DN, including renin–angiotensin–aldosterone system (RAAS) blockade, glucagon-like peptide-1 receptor agonists, non-steroidal mineralocorticoid receptor, and sodium-glucose cotransporter-2 (SGLT2) inhibitors, only slow the progression of the disease rather than reversing the pathology. Therefore, there is a growing interest in identifying alternative or complementary therapeutic agents, particularly those derived from natural products with multi-targeted activities. Psoralea corylifolia Linn (PCL) is a medicinal herb commonly used in traditional Asian medicine. It has known pharmacological properties on oxidative stress, inflammation, fibrosis and metabolic disorders. Accumulating recent studies indicated that PCL and its bioactive compounds, such as psoralen, bakuchiol, and corylin, mitigate pathological conditions in various diseases. Here, the current review will provide our current knowledge of major identified and characterized PCL focusing on their biological activity and function, particularly in DN. Full article

Kidney disease, be it acute or chronic, has a complex pathology and is a significant human health problem. Increasing interest has been focused on exploring therapeutic targets that can be used to safeguard kidney function under a variety of detrimental conditions. In this article, we review the protective effects of 5-methoxytryptophan (5-MTP), a tryptophan metabolite, on kidney injury. Published studies indicate that serum 5-MTP level is decreased in patients with chronic kidney disease (CKD), suggesting that 5-MTP is a biomarker for CKD and has therapeutic values. Indeed, rodent models of kidney injury induced by folic acid, lipopolysaccharide (LPS), unilateral ureteral obstruction (UUO), and ischemia/reperfusion all demonstrate that exogenous 5-MTP exhibits nephroprotective effects. The underlying mechanisms involve antioxidative damage via activating antioxidant systems such as heme oxygenase-1, anti-inflammation, anti-fibrosis, and enhanced mitophagy. To further explore the underlying mechanisms and the potential of 5-MTP as a kidney therapeutic compound, future studies need to include more rodent models of kidney injury induced by a variety of insults. Moreover, how to boost endogenous 5-MTP content and its potential synergistic effects with other therapeutic approaches aiming to combat kidney diseases also remain to be explored. Full article

Background: Liver fibrosis is a major global public health issue that is only getting worse. The underlying molecular mechanisms of Yindanpinggan Capsule (YDPG), a traditional Chinese medication, are still unknown, although it has shown notable effectiveness in treating fibrosis and other forms of liver injury. Methods: To evaluate the impact of YDPG on liver fibrosis, a mouse model of liver damage caused by carbon tetrachloride (CCL₄) was used. Proteomics, deep learning, network pharmacology, and later biological process validation using Western blot were used to elucidate the possible mechanism of YDPG in reducing liver damage. Results: Following YDPG treatment, we observed a decrease in the fibrosis index and an improvement in liver function. Network pharmacology, deep learning, and proteomics collectively identified the ferroptosis and peroxisome proliferator-activated receptor (PPAR) signaling pathways as pivotal in the anti-fibrosis effects of YDPG on the liver. Further experimental results showed that YDPG inhibited Malondialdehyde (MDA) and Fe²⁺ content and increased Glutathione (GSH) activity in fibrotic liver. Mechanistically, both SLC7A11/GSH pathway-mediated ferroptosis and oxidative stress up-regulated by the PPAR γ/GPx4 pathway were alleviated following YDPG treatment. Conclusions: Our present study corroborates that YDPG limits the progression of liver fibrosis by regulating the PPARγ-GPX4-ferroptosis pathway. These results indicate that YDPG could be a potential medication for hepatic fibrosis. 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

Through the mineralocorticoid receptor, aldosterone controls extracellular volume and arterial blood pressure by stimulating Na⁺ absorption and K⁺ secretion in epithelial cells of the kidney, colon, and several glands. Hyperaldosteronism promotes fibrosis and inflammation in epithelial and non-epithelial tissues, thereby favoring loss of kidney and heart function. Mineralocorticoid receptor blockade therefore gains relevance especially in renal and cardiac disease. Kidney-derived Klotho is a powerful anti-aging protein with anti-fibrosis and anti-inflammatory effects providing cardio- and nephroprotection. We wondered whether Klotho expression and production is influenced by mineralocorticoid receptor agonists and antagonists. Using four renal cell lines, Madin-Darby canine kidney (MDCK), normal rat kidney, subtype 52E (NRK-52E), human kidney 2 (HK2) cells, and primary renal proximal tubule epithelial cells (RPTECs), and the four most frequently prescribed mineralocorticoid receptor blockers, spironolactone, eplerenone, finerenone, and esaxerenone, we assessed Klotho gene expression by qRT-PCR and Klotho protein by Western blotting. Aldosterone and eplerenone did not significantly affect Klotho expression in either cell line. Spironolactone enhanced Klotho expression in MDCK and NRK-52E cells and downregulated Klotho in HK2 cells and RPTECs. Novel non-steroidal mineralocorticoid receptor antagonist finerenone downregulated Klotho expression in MDCK, NRK-52E, and low-dose finerenone in HK2 cells. To conclude, common mineralocorticoid receptor antagonists are characterized by highly diverse effects on Klotho in four renal cell lines. Further studies are needed to define the role of mineralocorticoid receptor blockade for Klotho production. Full article

Diabetic nephropathy (DNR) remains a major complication of type 2 diabetes with limited options to halt progression. We evaluated whether DNR (a sulfur-rich extract from Hongsan garlic) confers renoprotection in a db/db mouse model. Seventy male C57BLKS/J mice were randomized into seven groups (db/m control, db/db control, metformin 250 mg/kg, DNR 100/300/900 mg/kg, and metformin 250 mg/kg + DNR 300 mg/kg) and treated orally for eight weeks. Physiological, biochemical, urinary, histological, and immunohistochemical(IHC) endpoints were assessed, including serum creatinine, blood urea nitrogen(BUN), lipids, glucose, urinary microalbumin/albumin-to-creatinine ratio(ACR), glomerular area, mesangial expansion, and renal KIM-1 and TGF-β1 expression. Chemical profiling of the DNR extract by HPLC and LC–MS/MS identified allicin as a principal sulfur-containing constituent, exhibiting a distinct retention peak at 2.90 min and a protonated molecular ion at m/z 162.1 [M]⁺ with diagnostic fragment ions at m/z 145.1, 120.1, and 99.0. Allicin was qualitatively confirmed as a characteristic component of DNR, serving as a representative chemical marker for compositional characterization. DNR produced dose-dependent improvements: reductions in serum creatinine and BUN, improved lipid and glycemic profiles, decreased urinary microalbumin and ACR, and amelioration of glomerular hypertrophy and mesangial matrix expansion. IHC showed lower KIM-1 and TGF-β1 staining in treated groups. Effects at higher DNR doses were comparable to or additive with metformin for several endpoints. These findings indicate that DNR has promising renoprotective effects in this preclinical model. Full article

Background and Objectives: Idiopathic pulmonary fibrosis (IPF) is a fatal interstitial lung disease with few effective treatments. In its pathogenesis, damage-associated molecular patterns are released and recognized by Toll-like receptors (TLRs); all TLRs except TLR3 transduce signals through MyD88. Research has shown that autophagy participates in the progression of pulmonary fibrosis, and MyD88 is closely associated with autophagy. However, whether targeting MyD88 can affect fibrosis progression by regulating autophagy during lung fibrosis remains unclear. Materials and Methods: TJ-M2010-5 (TJ-5) is a small molecular derivative of aminothiazole that inhibits MyD88 homodimerization. A bleomycin-induced pulmonary fibrosis model in mice was established, and a human lung fibroblast cell line MRC-5 was cultured, and the mechanism of fibrosis induced by TGF-β1 was studied. TJ-5 and the autophagy inhibitor 3-MA were used to intervene. Results: Our study indicated that TJ-5 suppressed fibrosis foci formation and collagen deposition in fibrotic lungs, effectively increased the survival rate of bleomycin-stimulated mice from 40.0% to 80.0%, and repressed lung fibroblast activation in vitro. Subsequently, TJ-5 could trigger autophagy, as indicated by increased autophagosomes, LC3B-II and Beclin-1 promotion, and p62 degradation. Moreover, inhibition of TJ-5-induced autophagy by 3-MA reversed the anti-fibrosis effect of TJ-5. Furthermore, the autophagy-related pathways PI3K/AKT/mTOR and MAPK/mTOR were inhibited under TJ-5 intervention. Conclusions: Our findings demonstrated that the mechanism of TJ-5 in alleviating lung fibrosis was through triggering MyD88-related autophagy, and TJ-5 may be therapeutically useful for the clinical treatment of IPF. 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

Pulmonary fibrosis (PF) is a progressive and fatal interstitial lung disease characterized by chronic epithelial injury and excessive deposition of extracellular matrix (ECM) driven by dysregulated repair. Increasing evidence has shown that epithelial cell dysfunction plays a key role in PF, involving epithelial–mesenchymal transition (EMT), chronic oxidative stress, disruption of epithelial–immune interactions, and promoting pathological remodeling. Single-cell analyses have identified functionally distinct subpopulations of type 2 alveolar (AT2) cells with pro-fibrotic potential. Epithelial cells exhibit metabolic and epigenetic alterations during PF, which provide new approaches for therapeutic targets. This review summarizes the molecular mechanisms driving epithelial dysfunction in fibrosis progression, with a focus on key regulatory pathways, including transforming growth factor-beta (TGF-β), Wnt, and Notch signaling pathways, as well as miRNA-mediated networks. We also explored emerging epithelial-targeted therapies, ranging from FDA-approved agents (pirfenidone, nintedanib) to experimental inhibitors targeting Galectin-3 and Wnt/β-catenin, providing insights into precision anti-fibrosis strategies for clinical translation. Full article

Microcirculation damage, dermal thickening, and difficulty in the spatiotemporal coordination of key platelet factor 4 (CXCL4) and transforming growth factor-β (TGF-β) contribute to the lack of effective treatments for systemic sclerosis (scleroderma, SSc). To address these challenges, we proposed a novel synergistic drug combination of ginsenoside Rk3 (CXCL4 regulator) and metformin (Met, TGF-β regulator) based on molecular docking and developed an ultra-long release, dual-target regulation hydrogel microneedle system (Rk3/Met URS MN). The rapidly dissolving tips of this hydrogel microneedle consisted of polyvinyl alcohol and polyvinylpyrrolidone, and were loaded with polydopamine-coated, coordination-induced self-assembled Rk3/Met nanomedicines. These micro-tips could spatiotemporally synchronize transdermal delivery of the hydrophobic Rk3 and hydrophilic Met, providing ultra-long release for up to 10 days with a single administration. The recombinant collagen CF-1552/oxidized pullulan-based (CAOP) hydrogel backing exhibited skin self-adhesiveness and excellent mechanical properties and could perform localized moisture retention and free radical scavenging at the lesion site. In vitro and in vivo efficacy studies, along with bioinformatics analysis of RNA sequencing, demonstrated that the Rk3/Met URS MN achieved immune modulation, anti-inflammatory effects, angiogenesis promotion, and antifibrosis in SSc through synergistic CXCL4/TGF-β dual-target regulation. Notably, on the 10th day, the dermal thickness decreased from 248.97 ± 21.3 μm to 152.7 ± 18.1 μm, with no significant difference from the normal group, indicating its significant potential in clinical applications in SSc. Full article

Myocardial fibrosis (MF) is the excessive deposition of extracellular matrix (ECM) from myofibroblasts and is crucial in patients with heart failure (HF). Much work is still needed to fully understand its features and clinical role. This review aims to summarize the state-of-the-art of MF knowledge, focusing on assessment, quantification, predictive value, and future therapies. We performed a literature search about MF studies published between 2014 and 2024, including clinical studies on MF assessment or quantification, the role of MF as a prognostic factor in patients with HF, basic science studies on fibrosis assessment, and the role of the main mechanisms involved in MF. We identified 5161 potentially relevant articles. After excluding non-appropriate ones, we had 186 potentially suitable studies. After full reading and a review of references, 40 articles were included in our review: 8 were about MF assessment, 5 about quantification, and 27 about fibrosis as a prognostic factor. MF is a crucial process in patients with cardiac diseases and leads to HF and arrhythmias. Assessment and quantification have taken great steps forward, but more research is needed to strengthen MF’s role as a prognostic factor in the future. Basic science will play a key role in anti-fibrosis treatment. Full article

We showed that multiple inflammatory cytokines (e.g., CCL5, CXCL12, CX3CL1, CD40L, and FGF2) bind to the allosteric site (site 2) of integrins, distinct from the classical RGD-binding site (site 1), and allosterically activate integrins. A major inflammatory lipid mediator 25-hydroxycholesterol is known to bind to site 2 and allosterically activates integrins and induces inflammatory signals (e.g., IL-6 and TNF secretion). Thus, site 2 is involved in inflammatory signaling. Neuregulin-1 (NRG1) is known to suppresses the progression of inflammatory diseases, fibrosis, and insulin resistance. But, the mechanism of anti-inflammatory action of NRG1 is unclear. We previously showed that NRG1 binds to the classical RGD-binding site (site 1). Mutating the 3 Lys residues that are involved in site 1 binding (NRG1 3KE mutant) is defective in binding to site 1 and in ErbB3-mediated mitogenic signals. Docking simulation predicted that NRG1 binds to site 2. We hypothesized that NRG1 acts as an antagonist of site 2 and blocks allosteric activation by multiple cytokines. Here, we describe that NRG1 binds to site 2 but does not activate soluble αvβ3 or αIIbβ3 in 1 mM Ca²⁺, unlike inflammatory cytokines. Instead, NRG1 suppressed integrin activation by several inflammatory cytokines, suggesting that NRG1 acts as a competitive inhibitor of site 2. Wild-type NRG1 is not suitable for long-term treatment due to its mitogenicity. We showed that the non-mitogenic NRG1 3KE mutant still bound to site 2 and inhibited allosteric activation of soluble and cell-surface integrins, suggesting that NRG1 3KE may have potential as a therapeutic. Full article

Background: Activated hepatic stellate cells (aHSCs) play a significant role during the onset of hepatic fibrosis, ultimately leading to excessive deposition of extracellular matrix (ECM) and other typical pathological features, and thus have become a popular target for the treatment of hepatic fibrosis. However, current aHSC-centric therapy strategies achieve unsatisfactory results, mainly due to the lack of approved anti-fibrosis drugs and sufficiently efficient aHSC-targeted delivery systems. In this study, our aim was to develop an Imatinib-loaded nanoparticle delivery system based on a chondroitin sulfate derivative to enhance aHSC targeting efficiency, improve the therapeutic effect for hepatic fibrosis, and investigate the underlying mechanism. Methods: The carboxyl group of chondroitin sulfate and the amino group of 1-hexadecylamine were linked by an amide bond in this study to produce the amphiphilic carrier CS-HDA. Then, the Imatinib-loaded nanoparticles (IM-CS NPs) were designed to efficiently target aHSCs through CD44-mediated endocytosis and effectively inhibit HSC overactivation via PDGF and TGF-β signaling pathways. Results: Both in vitro cellular uptake experiments and in vivo distribution experiments demonstrated that CS-HDA-modified nanoparticles (IM-CS NPs) exhibited a better targeting ability for aHSCs, which were subsequently utilized to treat carbon tetrachloride-induced hepatic fibrosis mouse models. Finally, significant fibrosis resolution was observed in the carbon tetrachloride-induced hepatic fibrosis mouse models after tail vein injection of the IM-CS NPs, along with their outstanding biocompatibility and biological safety. Conclusions: IM-loaded NPs based on an amphiphilic CS derivative have remarkable antifibrotic effects, providing a promising avenue for the clinical treatment of advanced hepatic fibrosis. Full article

The gut microbiota influences and contributes to kidney health and disease. Butyrate, a short-chain fatty acid molecule generated via the fermentation of gut bacterial catabolism of nondigestible dietary fiber, has been shown to exert numerous beneficial effects on kidney disorders. The objective of this review was to discuss the latest findings on the protective effects of butyrate on a variety of animal models of kidney injury. We conducted a PubMed search using the title word “butyrate” and keyword “kidney” to generate our literature review sources. The animal models covered in this review include ischemia–reperfusion renal injury, cisplatin- and folic acid-induced kidney injury, septic kidney injury, diabetic kidney disease (DKD), high-fat diet (HFD)-induced glomerulopathy, adenine-induced chronic kidney disease (CKD), high-salt-induced renal injury, and T-2 toxin-induced kidney injury in birds. The protective mechanisms of butyrate that are most shared among these animal model studies include antioxidative stress, anti-fibrosis, anti-inflammation, and anti-cell death. This review ends with suggestions for future studies on potential approaches that may modulate gut microbiota butyrate production for the well-being of kidneys with the kidney disorders covered in this review. Full article