Recent studies have shown that the activation of the ROS-dependent NLRP3 inflammasome plays a key role in the pathogenesis of silicosis; however, the mechanism by which SiO2-induced ROS activates NLRP3 remains unclear. In this study, rats were intratracheally instilled with a SiO2 suspension once and then received daily intravenous injections of NAC (at doses of 20, 40, and 80 mg/kg, respectively) to inhibit SiO2-induced ROS. Rats that were intratracheally instilled with a SiO2 suspension once served as silicosis models, while those that were intratracheally instilled with PBS once served as controls. After 40 days, lung samples were taken for pathological observation, and the BALF was collected to measure ROS levels. The mRNA and protein expression levels of Keap1/Nrf2 signaling indicators (Keap1, Nrf2) and NLRP3 inflammasome indicators (NLRP3, GSDMD) were detected. The results showed that the Keap1/Nrf2 signaling pathway and the NLRP3 were activated in the silicosis rat lungs, accompanied by an increase in ROS levels. When ROS was inhibited, the Keap1/Nrf2 signaling pathway, the NLRP3, and the degree of pulmonary fibrosis were all suppressed in a dose-dependent manner. Therefore, we conclude that SiO2 particles induce pulmonary fibrosis in rats by modulating the NLRP3 inflammasome via the ROS/Keap1/Nrf2 signaling pathway.

Pulmonary fibrosis (PF) is a progressive and lethal interstitial lung disease characterized by aberrant scar formation and destruction of alveolar architecture. Dysfunctional alveolar epithelial cells (AECs) play a central role in initiating PF, where chronic injury triggers apoptosis and disrupts epithelial homeostasis, leading to epithelial-mesenchymal transition (EMT). This dynamic reprogramming process causes AECs to shed epithelial markers and adopt a mesenchymal phenotype, fueling fibroblast activation and pathological extracellular matrix (ECM) deposition. This review systematically explores the multi-layered mechanisms driving AECs dysfunction and EMT, focusing on core signaling axes such as transforming growth factor-β (TGF-β)/Smad, WNT/β-catenin, NF-κB-BRD4, and nuclear factor erythroid 2-related factor 2 (Nrf2), which regulate EMT and fibroblast-ECM interactions. It also highlights emerging regulators, including metabolic reprogramming, exosomal miRNA trafficking, and immune-epithelial interactions. Furthermore, understanding these mechanisms is essential for developing targeted therapeutic strategies to modulate these pathways and halt or reverse fibrosis progression, offering critical insights into potential clinical treatments for PF.

Pulmonary fibrosis (PF) is a chronic interstitial lung illness characterized by its high worldwide prevalence, unknown etiology, and dismal prognosis. Lonicerae Japonicae Flos, a commonly used traditional Chinese medicine for treating PF, is rich in Rhoifolin (ROF). Although numerous studies have demonstrated the anti-inflammatory properties of ROF, its potential anti-fibrotic effects remain uncertain.

In this study, we established a PF model in Sprague-Dawley (SD) rats utilizing Bleomycin (BLM). We then assessed the impact of ROF on lung histology and appearance, measured the content level of Superoxide dismutase (SOD) in rat serum, and analyzed changes in α-SMA, TGF-β relative mRNA expression using PCR, measured SMAD Family Member 7 (Smad7), and Heme Oxygenase-1 (HO-1) protein expression in rat lung tissue by Western Blot. Additionally, we induced a cell injury model in A549 cells with BLM. Then after ROF administration, we detected the cell viability by MTT assay, measured N-cadherin, α-SMA, and Vimentin mRNA levels via real-time PCR, and analyzed the expression changes of N-cadherin, Nuclear factor erythroid 2-related factor 2(Nrf2), HO-1, Smad7 proteins by Western Blot.

The results indicated that ROF mitigated lung tissue damage and reduced the degree of PF in the lung tissue of rats with PF. Furthermore, In vivo, ROF reduced the expression of N-cadherin protein while increasing the expression of Smad7, and HO-1 proteins and decreasing the relative mRNA expression of α-SMA and TGF-β, and increased the expresson of SOD in rat serum In vitro, cell injury was induced in A549 cells using BLM. After ROF administration, the relative mRNA expression of α-SMA, N-cadherin, and Vimentin decreased significantly, and the protein expression of N-cadherin decreased, while the protein expression of Nrf2, HO-1, and Smad7 increased significantly.

This study demonstrates that ROF can mitigate the symptoms of PF to a certain degree, and its mechanism of action is intimately linked to the Nrf2/HO-1 signaling pathway. Therefore, this study indicates that ROF may serve as a potential therapeutic agent for treating PF.

Not applicable.

Pulmonary fibrosis (PF) is a frequently reported COVID-19 sequela. It is a progressive disorder characterized by respiratory failure and death. The properties of Alpinia officinarum Rhizomes (AO) make it a highly potent antioxidant, anti-inflammatory, and antifibrotic agent. This study has evaluated AO's protective effects on bleomycin-induced PF in rats and investigated the underlying mechanisms.

Bleomycin (5mg/kg, intratracheally) was used to induce PF in albino rats, and then, AO extract (200mg/kg/daily, orally) was administrated for 28days post-bleomycin-instillation. After euthanizing the rats, the biochemical, quantitative real-time polymerase chain reaction (qPCR) and histopathological examination of lung tissue were determined.

Findings have revealed that bleomycin significantly increased the tissue level of malondialdehyde, tumor necrosis factor-alpha, and interleukin-6, Silent information regulator 1 (Sirt1), and nuclear factor erythroid 2-related factor 2 (Nrf2) mRNA levels. Furthermore, the total antioxidant capacity level decreased in the lungs of bleomycin-instilled rats. However, AO extract significantly decreased histopathological injuries in hematoxylin & eosin, Masson's trichrome-stained sections, inducible nitric oxide synthase and α-smooth muscle actin, transforming growth factor beta 1 immunoexpression.

Alpinia officinarum Rhizomes extract appears to protect against bleomycin-induced PF, possibly due to its antioxidant, anti-inflammatory, and antifibrotic properties.

Cigarette smoke (CS) has been demonstrated to mediate oxidative stress (OS) and epithelial-mesenchymal transition (EMT) in bronchial epithelial cells, thereby contributing to airway remodeling in chronic obstructive pulmonary disease (COPD). Studies have shown upregulation of Ubiquitin C-terminal hydrolase L1 (UCHL1), a deubiquitinating enzyme, in the airway epithelium of smokers. Many studies indicate that UCHL1's regulation of EMT and OS has a complex role in various cell types, including respiratory epithelium. Thus, we aimed to investigate UCHL1's regulation of EMT, OS, and related mechanisms in cigarette smoke-exposed airway epithelium.

Exposure to cigarette smoke (CS) or cigarette smoke extract (CSE) was employed to establish both animal and cellular models. Protein expression was analyzed using immunohistochemistry, immunofluorescence, and Western blotting. Lentiviral UCHL1 or GPX1-siRNA was used to modulate UCHL1 or GPX1 expression, respectively. Transwell assays were employed to evaluate cell migration and EMT-related alterations. Oxidative stress levels were assessed using specific assay kits.

This study validated that exposure to CS induces UCHL1 expression in bronchial epithelial cells both in vitro and in vivo, a phenomenon positively correlated with increased OS and EMT in the airway. Notably, UCHL1 overexpression counteracted CSE's impact on EMT markers, cell migration, and oxidative stress in BEAS-2B cells, while UCHL1 knockdown exacerbated these effects. Furthermore, in BEAS-2B cells treated with CSE, upregulation of UCHL1 was found to enhance the expression of glutathione peroxidase 1 (GPX1), an antioxidant enzyme. The effect of UCHL1 overexpression on EMT-related protein markers and cell migration was reversed upon GPX1 silencing via siRNA.

These findings suggest that UCHL1-mediated regulation of GPX1 expression alleviates cigarette smoke-induced EMT-related protein markers change and cell migration in BEAS-2B cell.

Sulforaphane (SFN) is a phytochemical bioactive substance commonly found in cruciferous plants, such as broccoli and mustard. It has been reported to possess antibacterial, anti-inflammatory, anti-oxidant, anti-cancer and autophagy regulating properties. Recent studies have revealed that SFN regulates fat metabolism both in vivo and in vitro through various mechanisms, including alleviating endoplasmic reticulum stress, inhibiting inflammatory response and improving mitochondrial dysfunction, involving Nrf2/ARE, NF-κB, NLRP3 inflammasome, HDAC8-PGC1α axis and other signaling pathways. By curbing complications associated with abnormal fat metabolic diseases, SFN exhibits therapeutic effects on conditions like obesity, fatty liver disease, atherosclerosis, type 2 diabetes, etc., with minimal side effects. Therefore, it holds promise as a potential alternative treatment for lipid metabolism-related diseases. Although its extraction method has been matured, the thermal instability and preservation difficulties of SFN limit its clinical promotion. More effective and low-cost methods to improve the stability and production of SFN remain to be further studied. This paper reviews the physiological and biological activities of SFN, and summarizes the protective effects and molecular mechanisms of SFN in diseases related to abnormal lipid metabolism. Additionally, it proposes potential challenges, possible solutions and future research directions in the clinical application of SFN.

Immune response gene 1 (IRG1) is highly expressed in mitochondria of macrophages in a pro-inflammatory state. IRG1 and its metabolites play important roles in infection, immune-related diseases and tumor progression by exerting resistance of pathogens, attenuating inflammation and producing antioxidant substances through various pathways and mechanisms. IRG1 deficiency aggravates liver injury. Efferocytosis is a vital mechanism for preventing the progression of inflammatory tissue damage. However, the mechanism by how IRG1/itaconate regulates efferocytosis in autoimmune hepatitis has yet to be fully understood. Therefore, we explored the influence of IRG1-/- on efferocytosis and its effects on regulating the nuclear factor erythroid 2-associated factor 2 (Nrf2)-T-cell immunoglobulin domain and mucin domain 4 (TIM4) pathway and autoimmune liver injury. An autoimmune hepatitis model was established by injecting Con A into wild-type and IRG1-/- mice via the tail vein. Liver injury and inflammatory response were assessed. The efferocytosis role of IRG1-/- macrophages and its potential regulatory mechanisms were also analysed. Exogenous 4-octyl itaconate (OI) supplementation promoted the expression of Nrf2 and TIM4 and restored IRG1-/- bone marrow-derived macrophage (BMDM) efferocytosis, whereas inhibition of Nrf2 mediated by ML385 led to impaired efferocytosis of BMDMs, decreased expression of TIM4, and aggravated liver inflammation injury. Additionally, after supplementing Nrf2-/- BMDMs with exogenous OI, we evaluated the changes in its efferocytosis effect, efferocytosis did not change, and the protective effect of OI disappeared. However, when TIM4 was blocked, the efferocytotic effect of BMDMs was attenuated, inflammatory liver injury and oxidative stress were aggravated. OI promoted the transformation of macrophages into M2 macrophages, and this was inhibited when TIM4 was blocked. To our best understanding, this is the initial exploration to show that TIM4, a downstream molecule of the IRG1/itaconate-Nrf2 pathway, regulates macrophage efferocytosis. These findings suggest a new mechanism and potential treatment for promoting the resolution of inflammation and efferocytosis in autoimmune hepatitis.

Fibrosis, an aberrant reparative response to tissue injury, involves a disruption in the equilibrium between the synthesis and degradation of the extracellular matrix, leading to its excessive accumulation within normal tissues, and culminating in organ dysfunction. Manifesting in the terminal stages of nearly all chronic ailments, fibrosis carries a high mortality rate and poses a significant threat to human health. Heme oxygenase-1 (HO-1) emerges as an endogenous protective agent, mitigating tissue damage through its antioxidant, anti-inflammatory, and antiapoptotic properties. Numerous studies have corroborated HO-1's potential as a therapeutic target in anti-fibrosis treatment. This review delves into the structural and functional attributes, and the upstream and downstream pathways of HO-1. Additionally, the regulatory networks and mechanisms of HO-1 in cells associated with fibrosis are elucidated. The role of HO-1 in various fibrosis-related diseases is also explored. Collectively, this comprehensive information serves as a foundation for future research and augments the viability of HO-1 as a therapeutic target for fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease with limited therapeutic options. Our previous research has shown that the Jinshui Huanxian formula (JHF) is effective in treating IPF. However, the biomechanical mechanisms of its refined components, known as the effective-component compatibility of JHF II (ECC-JHF II), are not well understood.

This study aims to explore how bioactive components from traditional Chinese medicine (TCM) impact the biomechanical progression of pulmonary fibrosis.

A mouse model of pulmonary fibrosis was established by a single intratracheal instillation of bleomycin (Bleomycin). Pulmonary function, pathological changes, collagen deposition, lung tissue stiffness, and EMT markers were evaluated at the end of the study. Polyethylene glycol hydrogels with adjustable stiffness were used to mimic both normal and pathological lung conditions. The effects of ECC-JHF II on matrix stiffness-mediated EMT were assessed by quantitative real-time PCR, western blot, and immunofluorescence. The biomechanical mechanisms underlying ECC-JHF II on EMT and pulmonary fibrosis were verified both in vivo and in vitro.

ECC-JHF II significantly improved bleomycin (Bleomycin)-induced pulmonary fibrosis in mice, manifested as increased tidal volume and 50 % tidal volume expiratory flow, reduced lung tissue stiffness, and decreased EMT markers. Histopathological analysis showed reduced inflammation, alveolar damage, and collagen deposition. In vitro, ECC-JHF II reversed the EMT phenotypic transition induced by substrate stiffness, demonstrated by the upregulation of E-cadherin, occludin, and zonula occluden-1, and the downregulation of N-cadherin, vimentin, caldesmon 1 and tropomyosin 1. Moreover, ECC-JHF II could inhibit integrin/ROCK/MRTF signaling in vitro and in vivo. Silencing integrin β1 or activating it with pyrintegrin further confirmed the role of integrin β1 in the mechanotransduction pathway and the efficacy of ECC-JHF II.

Taken together, the findings of this study indicate that ECC-JHF II exerts a therapeutic effect on pulmonary fibrosis through the attenuation of lung tissue stiffness and inhibition of EMT, potentially via the integrin/ROCK/MRTF signaling pathway.

Cellular senescence is an adverse factor in the development of pulmonary fibrosis (PF). Ginsenoside Rb1 has been found to inhibit both cellular senescence and PF. This study aimed to elucidate the molecular mechanisms by which ginsenoside Rb1 regulates cellular senescence and PF. A PF mouse model was established by Bleomycin (BLM) administration, and a cell model of senescence was constructed using MRC-5 cells treated with Adriamycin RD (ARD) administration. Hematoxylin and Eosin (HE) staining and Masson staining were employed to evaluate cellular structure and collagen fiber content. RT-qPCR and western blotting were used to detect mRNA and protein expression of the target genes. Enzyme-linked Immunosorbent Assay (ELISA) was applied to measure the protein concentration of IL-1[Formula: see text] and IL-18. SA-[Formula: see text]-gal staining was used to evaluate cellular senescence. Our results show that ginsenoside Rb1 effectively suppressed BLM-induced PF in mice. ARD administration to induce cellular senescence reduced NRF2, QKI, and SMAD7 expression in MRC-5 cells. By inducing NRF2 overexpression, ARD-induced cellular senescence and fibrosis in MRC-5 cells were relieved. Notably, NRF2 knockdown abolished the mitigating effects of ginsenoside Rb1 on ARD-induced cellular senescence and fibrosis in MRC-5 cells. Mechanistically, NRF2 increased SMAD7 mRNA stability through the transcriptional regulation of QKI. As expected, ginsenoside Rb1 alleviated ARD-induced senescence and fibrosis in MRC-5 cells by activating the NRF2/QKI/SMAD7 axis. Therefore, it was found that ginsenoside Rb1 mitigates cellular senescence and fibrosis during PF progression by activating the NRF2/QKI/SMAD7 axis. This study provides a potential therapeutic strategy for the treatment of PF and elucidates its mechanism of action.

Silicosis is an occupational disease caused by long-term inhalation of free silica, resulting in a significant global health burden. Its pathogenesis remains unclear, and there is no effective treatment. Proliferative and activated myofibroblasts play a key role in the development of silicosis. Traditional studies have focused on fibroblast proliferation and collagen secretion, neglecting their functional heterogeneity. With the advancement of omics research, more pathogenic fibroblast subgroups and their functions have been identified. In this study, we applied transcriptomics to analyze gene changes in primary lung fibroblasts during silicosis development using a mouse model. Our results indicate that DEGs are enriched in collagen secretion, ECM synthesis, leukocyte migration, and chemotaxis functions. Altered core genes are associated with immune cell recruitment and cell migration. Nrf2 agonists, known for anti-inflammatory and antioxidant properties, have shown potential therapeutic effects in fibrotic diseases. However, their effects on fibroblasts in silicosis are not fully understood. We used four common Nrf2 agonists to study gene expression changes in lung fibroblasts at the transcriptome level, combined with histopathological and biochemical methods, to investigate their effects on silicosis in mice. Results show that Nrf2 agonists can exert anti-silicosis fibrosis functions by downregulating genes like Fos and Egr1, involved in cell differentiation, proliferation, and inflammation. In conclusion, this study suggests that inflammation-related co-functions of fibroblasts may be a potential mechanism in silicosis pathogenesis. Targeting Nrf2 may be a promising strategy to alleviate oxidative stress and inflammation in silicosis.

Gentamicin is one of the most common ototoxic drugs that can lower patients' quality of life. Oxidative stress is a key factors inducing sensory hair cell death during gentamicin administration. So far, there are no effective drugs to prevent or treat gentamicin- induced hearing loss. A recent study found cystic fibrosis transmembrane conductance regulator (CFTR) as a new target to modulate cellular oxidative balance. The objective of this study was to estimate the effect of the CFTR activator ivacaftor on gentamicin-induced ototoxicity and determine its mechanism.

The hair cell count was analyzed by Myosin 7a staining. Apoptosis was analyzed by TUNEL Apoptosis Kit. Cellular reactive oxygen species (ROS) level was detected by DCFH-DA probes. The Nrf2 related proteins expression levels were analyzed by western blot.

An in vitro cochlear explant model showed that gentamicin caused ROS accumulation in sensory hair cells and induced apoptosis, and this effect was alleviated by pretreatment with ivacaftor. Western blotting showed that ivacaftor administration markedly increased the protein expression of nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO1), and NAD(P)H:quinone oxidoreductase 1 (NQO1). The protective effect of ivacaftor was abolished by the Nrf2 inhibitor ML385.

Our results indicate the protective role of the CFTR-Nrf2-HO1/NQO1 pathway in gentamicin-induced ototoxicity. Ivacaftor may be repositioned or repurposed towards aminoglycosides-induced hearing loss.

Methotrexate (MTX)-induced pulmonary fibrosis is associated with high morbidity and mortality, with limited treatment options available. This study investigates whether disulfiram (DSF) can mitigate MTX-induced pulmonary fibrosis and explores the underlying mechanisms.

Eight-week-old male mice were divided into control, DSF, MTX, and MTX+DSF groups and treated for 8 weeks. Weight, food, and water intake were monitored. Post-treatment, lung tissues were analyzed using HE and Masson staining, and electron microscopy. Real-time qPCR and ELISA were employed to assess inflammatory markers such as IL-1β and TNF-α in lung tissues and serum. PCR, ELISA, and Western blot were used for fibrotic markers including Col1α1, α-SMA, and hydroxyproline. Type 2 alveolar epithelial cell line MLE12 cells were similarly grouped, followed by RNA sequencing and bioinformatics analysis to elucidate the mechanisms by which DSF exerts anti-MTX-induced pulmonary fibrosis effects. ELISA and Western blot were used to measure E-cadherin and α-SMA expression.

DSF significantly reduced MTX-induced alveolar septal thickening, pulmonary fibrosis, and inflammatory cell infiltration. It also decreased the expression of inflammatory factors IL-1β and TNF-α, as well as the expression of Col1α1, α-SMA, and others. RNA-seq revealed that DSF induces changes in multiple signaling pathways associated with pulmonary fibrosis, particularly in extracellular matrix-related genes. ELISA and Western blot showed decreased E-cadherin and increased α-SMA in the MTX group, which was partially restored with DSF treatment.

DSF alleviates MTX-induced pulmonary fibrosis by reducing epithelial-mesenchymal transition (EMT) in type 2 alveolar epithelial cells. Disulfiram shows potential as a therapeutic agent for MTX-induced pulmonary fibrosis.

Despite the tremendous advancements in the knowledge of the pathophysiology and clinical aspects of SARS-CoV-2 infection, still many issues remain unanswered, especially in the long-term effects. Mounting evidence suggests that pulmonary fibrosis (PF) is one of the most severe complications associated with COVID-19. Therefore, understanding the molecular mechanisms behind its development is helpful to develop successful therapeutic strategies. Epithelial to mesenchymal transition (EMT) and its cell specific variants endothelial to mesenchymal transition (EndMT) and mesothelial to mesenchymal transition (MMT) are physio-pathologic cellular reprogramming processes induced by several infectious, inflammatory and biomechanical stimuli. Cells undergoing EMT acquire invasive, profibrogenic and proinflammatory activities by secreting several extracellular mediators. Their activity has been implicated in the pathogenesis of PF in a variety of lung disorders, including idiopathic pulmonary fibrosis (IPF) and COVID-19. Aim of this article is to provide an updated survey of the cellular and molecular mechanisms, with emphasis on EMT-related processes, implicated in the genesis of PF in IFP and COVID-19.

Pulmonary fibrosis (PF) is a persistent interstitial lung condition for which effective treatment options are currently lacking. Zerumbone (zerum), a humulane sesquiterpenoid extracted from Zingiber zerumbet Smith, has been documented in previous studies to possess various pharmacological benefits. The aim of this study was to observe and investigate the therapeutic effects and mechanisms of zerum on pulmonary fibrosis. We utilized a transforming growth factor (TGF)-β1-induced human lung fibroblast (MRC-5) activation model and a bleomycin-induced pulmonary fibrosis mouse model. Cell counting kit 8 (CCK8) and cell migration assays were performed to assess the effects of zerum on MRC-5 cells. Masson's trichrome, Hematoxylin and Eosin (HE), and Sirius Red staining were conducted for pathological evaluation of lung tissue. Western blot experiments were conducted to measure the protein expression levels of Collagen I, α-SMA, Nrf2, and SIRT1. Immunofluorescence and immunohistochemistry assays were used to detect the expression of reactive oxygen species (ROS), Nrf2, and α-SMA. ELISA was employed to measure the levels of MDA, SOD, and GSH-Px. Our findings from in vitro and in vivo studies demonstrated that zerum significantly inhibited the migration ability of TGF-β1-induced MRC-5 cells, reduced ROS production in TGF-β1-induced MRC-5 cells and pulmonary fibrosis mice, and decreased the expression of Collagen I and α-SMA proteins. Additionally, zerum activated the SIRT1/Nrf2 signaling pathway in TGF-β1-induced MRC-5 cells and pulmonary fibrosis mice. Knockdown of SIRT1 abolished the anti-fibrotic effects of zerum. These results suggest that zerum inhibits TGF-β1 and BLM-induced cell and mouse pulmonary fibrosis by activating the SIRT1/Nrf2 pathway.

Idiopathic pulmonary fibrosis (IPF) is a fatal respiratory disease characterized by chronic, progressive scarring of the lung parenchyma, leading to an irreversible decline in lung function. Apart from supportive care, there is currently no specific treatment available to reverse the disease. Based on the fact that tanshinone IIA (TAN) had an effect on protecting against TGF-β1-induced fibrosis through the inhibition of Smad and non-Smad signal pathways to avoid myofibroblasts activation, this study reported the development of the inhalable tanshinone IIA-loaded chitosan-oligosaccharides-coated poly(lactic-co-glycolic acid) (PLGA) nanoparticles (CPN@TAN) for enhancing the pulmonary delivery of tanshinone IIA to treat pulmonary fibrosis. The CPN@TAN with a size of 206.5 nm exhibited excellent in vitro aerosol delivery characteristics, featuring a mass median aerodynamic diameter (MMAD) of 3.967 ± 0.025 μm and a fine particle fraction (FPF) of 70.516 ± 0.929%. Moreover, the nanoparticles showed good stability during atomization and enhanced the mucosal penetration capabilities. The results of confocal spectroscopy confirmed the potential of the nanoparticles as carriers that facilitated the uptake of drugs by NIH3T3, A549, and MH-S cells. Additionally, the nanoparticles demonstrated good in vitro biocompatibility. In a mouse model of bleomycin-induced pulmonary fibrosis, noninvasive inhalation of aerosol CPN@TAN greatly suppressed collagen formation and facilitated re-epithelialization of the destroyed alveolar epithelium without causing systemic toxicity compared with intravenous administration. Consequently, our noninvasive inhalation drug delivery technology based on polymers may represent a promising paradigm and open the door to overcoming the difficulties associated with managing pulmonary fibrosis.

Abrus cantoniensis Polysaccharides (ACP) exhibit antioxidant activity and immune-regulatory functions. Abrus cantoniensis Hance widely distributed in the Guangdong and Guangxi regions of China. In this study, this research investigated the impact of phosphorylation modification on the biological activity of ACP, aiming to provide theoretical insights for its development. This research modified ACP through phosphorylation and evaluated changes in its in vitro antioxidant capacity, including free radical scavenging and resistance to cellular oxidative damage. Additionally, this research administered both native ACP and phosphorylated ACP (P-ACP) to mice to assess their protective effects against acute ethanol-induced oxidative injury. This research explored whether these effects were mediated through the Keap1-Nrf2 signaling pathway and their influence on gut microbiota. Results revealed that phosphorylation significantly enhanced ACP's antioxidant capacity and protective effects (p < 0.05). P-ACP improved mice resistance to acute oxidative injury, mitigating the adverse effects of 50 % ethanol (p < 0.05). Moreover, both ACP and P-ACP are involved in modulating the expression of the Keap1-Nrf2 signaling pathway and, to some extent, alter the composition of the gut microbiota in mice. In summary, phosphorylation modification effectively enhances ACP's antioxidant capacity and provides better protection against acute oxidative injury in mice.

This study looked at the role of anti-carbamylated protein (anti-CarP) antibodies in contributing to lung fibrosis in CTD-associated interstitial lung disease (ILD) in an autoantigen-dependent manner.

ELISA was used to test serum samples, including 89 from the CTD-ILD group and 170 from the non-CTD-ILD group, for anti-CarP levels. Male C57BL/6 mice were used for the pulmonary fibrosis model and anti-CarP treatment in vivo (n = 5) and patient serum-derived or commercialized anti-CarP was used for cell treatment. We identified the carbamylated membrane protein via immunofluorescence (IF) and co-immunoprecipitation followed by mass spectrometry (MS) analysis. Quantitative RT-PCR, IF and western blot were performed to explore the antigen-dependent role of anti-CarP. A native electrophoretic mobility shift assay and MS analysis were used to verify direct interaction and carbamylation sites.

A significantly higher serum anti-CarP level was observed in CTD with ILD than without ILD. In vivo, intrapulmonary delivery of anti-CarP induces epithelial-mesenchymal transition (EMT) and microfibrotic foci. Carbamylation was enriched in type II alveolar epithelial cells (AEC II). A novel carbamylated membrane receptor, specifically recognized by anti-CarP, was identified as toll-like receptor 5 (TLR5). We found anti-CarP induces the nuclear translocation of NF-κB and downstream events, including EMT and expression of inflammatory cytokines in AEC II, which were reversed by TLR5 blocking or TLR5 knockdown. Moreover, up to 12 lysine carbamylation sites were found in TLR5 ectodomain, allowing the interaction of anti-CarP with carbamylated TLR5.

Overall, we found anti-CarP drives aberrant AEC II activation by interacting with carbamylated TLR5 to promote ILD progression.

Osteoarthritis (OA) is a progressive joint disease characterized by extracellular matrix (ECM) degradation and inflammation, which is involved with pathological microenvironmental alterations induced by damaged chondrocytes. However, current therapies are not effective in alleviating the progression of OA. Isoquercetin is a natural flavonoid glycoside compound that has various pharmacological effects including anticancer, anti-diabetes and blood lipid regulation. Previous evidence suggests that isoquercetin has anti-inflammatory properties in various diseases, but its effect on OA has not been investigated yet. In this study, through western bolt, qRT-PCR and ELISA, it was found that isoquercetin could reduce the increase of ADAMTS5, MMP13, COX-2, iNOS and IL-6 induced by IL-1β, suggesting that isoquercetin could inhibit the inflammation and ECM degradation of chondrocytes. Through nuclear-plasma separation technique, western blot and immunocytochemistry, it can be found that Nrf2 and NF-κB pathways are activated in this process, and isoquercetin may rely on this process to play its protective role. In vivo, the results of X-ray and SO staining show that intra-articular injection of isoquercetin reduces the degradation of cartilage in the mouse OA model. In conclusion, the present work suggests that isoquercetin may benefit chondrocytes by regulating the Nrf2/NF-κB signaling axis, which supports isoquercetin as a potential drug for the treatment of OA.

Pulmonary fibrosis (PF) is the end stage of lung injury and chronic lung diseases that results in diminished lung function, respiratory failure, and ultimately mortality. Despite extensive research, the pathogenesis of this disease remains elusive, and effective therapeutic options are currently limited, posing a significant clinical challenge. In addition, research on traditional Chinese medicine and naturopathic medicine is hampered by several complications due to complex composition and lack of reference compounds. Natural product monomers, possessing diverse biological activities and excellent safety profiles, have emerged as potential candidates for preventing and treating PF. The effective anti-PF ingredients identified can be generally divided into flavonoids, saponins, polysaccharides, and alkaloids. Specifically, these monomeric compounds can attenuate inflammatory response, oxidative stress, and other physiopathological processes of the lung through many signaling pathways. They also improve pulmonary factors. Additionally, they ameliorate epithelial-mesenchymal transition (EMT) and fibroblast-myofibroblast transdifferentiation (FMT) by regulating multiple signal amplifiers in the lungs, thereby mitigating PF. This review highlights the significant role of monomer compounds derived from natural products in reducing inflammation, oxidative stress, and inhibiting EMT process. The article provides comprehensive information and serves as a solid foundation for further exploration of new strategies to harness the potential of botanicals in the treatment of PF.

Idiopathic pulmonary fibrosis is an aging-related, chronic lung disease, with unclear pathogenesis and no effective treatment. One of the triggering factors in cell aging is oxidative stress and it is known to have a role in idiopathic pulmonary fibrosis. In this paper, the protective effect of the E-CG-01 (3,4-lacto-cycloastragenol) molecule in terms of its antioxidant properties was evaluated in the bleomycin induced mice lung fibrosis model. Bleomycin sulfate was administered as a single dose (2.5 U/kg body weight) intratracheally to induce lung fibrosis. E-CG-01 was administered intraperitoneally in three different doses (2 mg/kg/day, 6 mg/kg/day, and 10 mg/kg/day) for 14 days, starting three days before the bleomycin administration. Fibrosis was examined by Hematoxylin-Eosin, Masson Trichrome, and immunohistochemical staining for TGF-beta1, Type I collagen Ki-67, and gama-H2AX markers. Activity analysis of catalase and Superoxide dismutase enzymes, measurement of total oxidant, total glutathione, and Malondialdehyde levels. In histological analysis, it was determined that all three different doses of the molecule provided a prophylactic effect against the progression of fibrosis compared to the bleomycin control group. However, it was observed that only the molecule applied in the high dose decreased the total oxidant stress level. Lung weight ratio increased in the BLM group but significantly reduced with high-dose E-CG-01. E-CG-01 at all doses reduced collagen deposition, TGF-β expression, and Ki-67 expression compared to the BLM group. Intermediate and high doses of E-CG-01 also significantly reduced alveolar wall thickness and edema formation. These findings suggest that E-CG-01 has potential therapeutic effects in mitigating lung fibrosis through its antioxidant properties.

To investigate the role and mechanism of epithelial-mesenchymal transition (EMT) in a rat model of bronchopulmonary dysplasia (BPD).

The experiment consisted of two parts. (1) Forty-eight preterm rats were randomly divided into a normoxia group and a hyperoxia group, with 24 rats in each group. The hyperoxia group was exposed to 85% oxygen to establish a BPD model, while the normoxia group was kept in room air at normal pressure. Lung tissue samples were collected on days 1, 4, 7, and 14 of the experiment. (2) Rat type II alveolar epithelial cells (RLE-6TN) were randomly divided into a normoxia group (cultured in air) and a hyperoxia group (cultured in 95% oxygen), and cell samples were collected 12, 24, and 48 hours after hyperoxia exposure. Hematoxylin-eosin staining was used to observe alveolarization in preterm rat lungs, and immunofluorescence was used to detect the co-localization of surfactant protein C (SPC) and α-smooth muscle actin (α-SMA) in preterm rat lung tissue and RLE-6TN cells. Quantitative real-time polymerase chain reaction and protein immunoblotting were used to detect the expression levels of EMT-related mRNA and proteins in preterm rat lung tissue and RLE-6TN cells.

(1) Compared with the normoxia group, the hyperoxia group showed blocked alveolarization and simplified alveolar structure after 7 days of hyperoxia exposure. Co-localization of SPC and α-SMA was observed in lung tissue, with decreased SPC expression and increased α-SMA expression in the hyperoxia group at 7 and 14 days of hyperoxia exposure compared to the normoxia group. In the hyperoxia group, the mRNA and protein levels of TGF-β1, α-SMA, and N-cadherin were increased, while the mRNA and protein levels of SPC and E-cadherin were decreased at 7 and 14 days of hyperoxia exposure compared to the normoxia group (P<0.05). (2) SPC and α-SMA was observed in RLE-6TN cells, with decreased SPC expression and increased α-SMA expression in the hyperoxia group at 24 and 48 hours of hyperoxia exposure compared to the normoxia group. Compared to the normoxia group, the mRNA and protein levels of SPC and E-cadherin in the hyperoxia group were decreased, while the mRNA and protein levels of TGF-β1, α-SMA, and E-cadherin in the hyperoxia group increased at 48 hours of hyperoxia exposure (P<0.05).

EMT disrupts the tight connections between alveolar epithelial cells in a preterm rat model of BPD, leading to simplified alveolar structure and abnormal development, and is involved in the development of BPD. Citation:Chinese Journal of Contemporary Pediatrics, 2024, 26(7): 765-773.

The lungs are a principal factor in the increased morbidity and mortality observed in patients with Connective Tissue Disease (CTD), frequently presenting as CTD-associated Interstitial Lung Disease (ILD). Currently, there is a lack of comprehensive descriptions of the pulmonary cells implicated in the development of CTD-ILD. This review leverages the Human Lung Cell Atlas (HLCA) and spatial multi-omics atlases to discuss the advancements in research on the pathogenesis of CTD-ILD from a pulmonary cell perspective. This facilitates a more precise localization of disease sites and a more systematic consideration of disease progression, supporting further mechanistic studies and targeted therapies.

 Metabolic-associated fatty liver disease (MAFLD) is a common cause of chronic liver disease worldwide. However, there is currently no recognized effective drugs for treating it.

 In this study, we investigated the efficacy of Honokiol (HNK) in vitro for mitigating MAFLD. Then, 0.4 mM palmitic acid (PA) and LO2 cells were used to establish the MAFLD model. The protective effect of HNK on MAFLD was confirmed by Oil Red O staining and cell counting kit (CCK-8) assay in LO2 cell line. Quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot were carried out to analyze the regulatory role of HNK on Nrf2 and RIPK3 signaling pathways. The effect of HNK and its downstream signaling pathways on oxidative stress were verified by the detection of reactive oxygen species (ROS), malondialdehyde (MDA), catalase (CAT), and superoxide dismutase (SOD). The concentration of IL-1β, IL-6L, and TNF-α was assessed by enzyme-linked immunosorbent assay (ELISA).

 The middle concentration of HNK (50 μmol/L) was selected as the best option for inhibiting lipidosis and oxidative stress in MAFLD models. Honokiol mitigates MAFLD via activation of nuclear factor E2-related factor 2 (Nrf2) signaling pathways in vitro. Honokiol suppressed MAFLD via activating the Nrf2 signaling pathway to play an antioxidant and anti-inflammatory role. Also, HNK regulates Nrf2 and RIPK3 signaling pathways to mitigate MAFLD.

 Our results showed that HNK may suppress the oxidative stress and inflammation in MAFLD via activation of Nrf2 signaling pathway.

Pulmonary fibrosis (PF) is a chronic interstitial lung disease characterized by fibroblast proliferation and extracellular matrix formation, causing structural damage and lung failure. Stem cell therapy and mesenchymal stem cells-extracellular vesicles (MSC-EVs) offer new hope for PF treatment.

To investigate the therapeutic potential of MSC-EVs in alleviating fibrosis, oxidative stress, and immune inflammation in A549 cells and bleomycin (BLM)-induced mouse model.

The effect of MSC-EVs on A549 cells was assessed by fibrosis markers [collagen I and α-smooth muscle actin (α-SMA), oxidative stress regulators [nuclear factor E2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1), and inflammatory regulators [nuclear factor-kappaB (NF-κB) p65, interleukin (IL)-1β, and IL-2]. Similarly, they were assessed in the lungs of mice where PF was induced by BLM after MSC-EV transfection. MSC-EVs ion PF mice were detected by pathological staining and western blot. Single-cell RNA sequencing was performed to investigate the effects of the MSC-EVs on gene expression profiles of macrophages after modeling in mice.

Transforming growth factor (TGF)-β1 enhanced fibrosis in A549 cells, significantly increasing collagen I and α-SMA levels. Notably, treatment with MSC-EVs demonstrated a remarkable alleviation of these effects. Similarly, the expression of oxidative stress regulators, such as Nrf2 and HO-1, along with inflammatory regulators, including NF-κB p65 and IL-1β, were mitigated by MSC-EV treatment. Furthermore, in a parallel manner, MSC-EVs exhibited a downregulatory impact on collagen deposition, oxidative stress injuries, and inflammatory-related cytokines in the lungs of mice with PF. Additionally, the mRNA sequencing results suggested that BLM may induce PF in mice by upregulating pulmonary collagen fiber deposition and triggering an immune inflammatory response. The findings collectively highlight the potential therapeutic efficacy of MSC-EVs in ameliorating fibrotic processes, oxidative stress, and inflammatory responses associated with PF.

MSC-EVs could ameliorate fibrosis in vitro and in vivo by downregulating collagen deposition, oxidative stress, and immune-inflammatory responses.

Abnormal glucose homeostasis is associated with metabolic syndromes including cardiovascular diseases, hypertension, type 2 diabetes mellitus, and obesity, highlighting the significance of maintaining a balanced glucose level for optimal biological function. This highlights the importance of maintaining normal glucose levels for proper biological functioning. Sulforaphane (SFN), the primary bioactive compound in broccoli from the Cruciferae or Brassicaceae family, has been shown to enhance glucose homeostasis effectively while exhibiting low cytotoxicity. This paper assesses the impact of SFN on glucose homeostasis in vitro, in vivo, and human trials, as well as the molecular mechanisms that drive its regulatory effects. New strategies have been proposed to enhance the bioavailability and targeted delivery of SFN in order to overcome inherent instability. The manuscript also covers the safety evaluations of SFN that have been documented for its production and utilization. Hence, a deeper understanding of the favorable influence and mechanism of SFN on glucose homeostasis, coupled with the fact that SFN is abundant in the human daily diet, may ultimately offer theoretical evidence to support its potential use in the food and pharmaceutical industries.

Spinal cord injury (SCI) is a traumatic injury to the central nervous system and can cause lipid peroxidation in the spinal cord. Ferroptosis, an iron-dependent programmed cell death, plays a key role in the pathophysiology progression of SCI. Celastrol, a widely used antioxidant drug, has potential therapeutic value for nervous system.

To investigate whether celastrol can be a reliable candidate for ferroptosis inhibitor and the molecular mechanism of celastrol in repairing SCI by inhibiting ferroptosis.

First, a rat SCI model was constructed, and the recovery of motor function was observed after treatment with celastrol. The regulatory effect of celastrol on ferroptosis pathway Nrf2-xCT-GPX4 was detected by Western blot and immunofluorescence. Finally, the ferroptosis model of neurons and oligodendrocytes was constructed in vitro to further verify the mechanism of inhibiting ferroptosis by celastrol.

Our results demonstrated that celastrol promoted the recovery of spinal cord tissue and motor function in SCI rats. Further in vitro and in vivo studies showed that celastrol significantly inhibited ferroptosis in neurons and oligodendrocytes and reduced the accumulation of ROS. Finally, we found that celastrol could inhibit ferroptosis by up-regulating the Nrf2-xCT-GPX4 axis to repair SCI.

Celastrol effectively inhibits ferroptosis after SCI by upregulating the Nrf2-xCT-GPX4 axis, reducing the production of lipid ROS, protecting the survival of neurons and oligodendrocytes, and improving the functional recovery.

Limonin is a natural tetracyclic triterpenoid compound in citrus seeds that presents hepatoprotective effects but is often discarded as agricultural waste because of its low content and low solubility. Herein, limonin with high purity (98.11%) from citrus seeds was obtained via purification by high-speed counter-current chromatography (HSCCC) and recrystallization. Limonin-loaded liposomes (Lip-LM) prepared by thin film hydration and high pressure homogenization method to enhance its solubility and hepatoprotective effect on APAP-induced liver injury (AILI). Lip-LM appeared as lipid nanoparticles under a transmission electron microscope, and showed well dispersed nano-scale size (69.04 ± 0.42 nm), high encapsulation efficiency (93.67% ± 2.51%), sustained release, fine stability. Lip-LM also exhibited significantly better hepatoprotective activity on AILI than free limonin in vivo. In summary, Lip-LM might be used as a potential hepatoprotective agent in the form of dietary supplement and provide an effective strategy to improve the potential value of citrus seeds.

Pulmonary fibrosis (PF) is a progressive lung disorder with a high mortality rate; its therapy remains limited due to the inefficiency of drug delivery. In this study, the system of drug delivery of nintedanib (Nin) by exosomes derived from adipose-derived stem cells (ADSCs-Exo, Exo) was developed to effectively deliver Nin to lung lesion tissue to ensure enhanced anti-fibrosis therapy.

The bleomycin (BLM)-induced PF model was constructed in vivo and in vitro. The effects of Exo-Nin on BLM-induced PF and its regulatory mechanism were examined using RT-qPCR, Western blotting, immunofluorescence, and H&E staining.

We found Exo-Nin significantly improved BLM-induced PF in vivo and in vitro compared to Nin and Exo groups alone. Mechanistically, Exo-Nin alleviated fibrogenesis by suppressing endothelial-mesenchymal transition through the down-regulation of the TGF-β/Smad pathway and the attenuation of oxidative stress in vivo and in vitro.

Utilizing adipose stem cell-derived exosomes as carriers for Nin exhibited a notable enhancement in therapeutic efficacy. This improvement can be attributed to the regenerative properties of exosomes, indicating promising prospects for adipose-derived exosomes in cell-free therapies for PF.

The system of drug delivery of nintedanib (Nin) by exosomes derived from adipose-derived stem cells was developed to effectively deliver Nin to lung lesion tissue to ensure enhanced anti-fibrosis therapy. The use of adipose stem cell-derived exosomes as the carrier of Nin may increase the therapeutic effect of Nin, which can be due to the regenerative properties of the exosomes and indicate promising prospects for adipose-derived exosomes in cell-free therapies for PF.

Radiation-induced lung injury (RILI) is a common and fatal complication of chest radiotherapy. The underlying mechanisms include radiation-induced oxidative stress caused by damage to the deoxyribonucleic acid (DNA) and production of reactive oxygen species (ROS), resulting in apoptosis of lung and endothelial cells and recruitment of inflammatory cells and myofibroblasts expressing NADPH oxidase to the site of injury, which in turn contribute to oxidative stress and cytokine production. Nuclear factor erythroid 2-related factor 2 (Nrf-2) is a vital transcription factor that regulates oxidative stress and inhibits inflammation. Studies have shown that Nrf-2 protects against radiation-induced lung inflammation and fibrosis. This review discusses the protective role of Nrf-2 in RILI and its possible mechanisms.

Idiopathic pulmonary fibrosis is a persistent disease of the lung interstitium for which there is no efficacious pharmacological therapy. Protodioscin, a steroidal saponin, possesses diverse pharmacological properties; however, its function in pulmonary fibrosis is yet to be established. Hence, in this investigation, it was attempted to figure out the anti-pulmonary fibrosis influences of protodioscin and its pharmacological properties related to oxidative stress.

A mouse lung fibrosis model was generated using tracheal injections of bleomycin, followed by intraperitoneal injection of different concentrations of protodioscin, and the levels of oxidative stress and fibrosis were detected in the lungs. Multiple fibroblasts were treated with TGF-β to induce their transition to myofibroblasts. It was attempted to quantify myofibroblast markers' expression levels and reactive oxygen species levels as well as Nrf2 activation after co-incubation of TGF-β with fibroblasts and different concentrations of protodioscin. The influence of protodioscin on the expression and phosphorylation of p62, which is associated with Nrf2 activation, were detected, and p62 related genes were predicted by STRING database. The effects of Nrf2 inhibitor or silencing of the Nrf2, p62 and NBR1 genes, respectively, on the activation of Nrf2 by protodioscin were examined. The associations between p62, NBR1, and Keap1 in the activation of Nrf2 by protodioscin was demonstrated using a co-IP assay. Nrf2 inhibitor were used when protodioscin was treated in mice with pulmonary fibrosis and lung tissue fibrosis and oxidative stress levels were detected.

In vivo, protodioscin decreased the levels of fibrosis markers and oxidative stress markers and activated Nrf2 in mice with pulmonary fibrosis, and these effects were inhibited by Nrf2 inhibitor. In vitro, protodioscin decreased the levels of myofibroblast markers and oxidative stress markers during myofibroblast transition and promoted Nrf2 downstream gene expression, with reversal of these effects after Nrf2, p62 and NBR1 genes were silenced or Nrf2 inhibitors were used, respectively. Protodioscin promoted the binding of NBR1 to p62 and Keap1, thereby reducing Keap1-Nrf2 binding.

The NBR1-p62-Nrf2 axis is targeted by protodioscin to reduce oxidative stress and inhibit pulmonary fibrosis.

Pulmonary fibrosis (PF) threatens millions of people worldwide with its irreversible progression. Although the underlying pathogenesis of PF is not fully understood, there is evidence to suggest that the disease can be blocked at various stages. Inhalation therapy has been applied for lung diseases such as asthma and chronic obstructive pulmonary disease, and its application for treating PF is currently under consideration. New techniques in inhalation therapy, such as the application of microparticles and nanoparticles, traditional Chinese medicine monomers, gene therapy, inhibitors, or agonists of signaling pathways, extracellular vesicle interventions, and other specific drugs, are effective in treating PF. However, the safety and effectiveness of these therapeutic techniques are influenced by the properties of inhaled particles, biological and pathological barriers, and the type of inhalation device used. This review provides a comprehensive overview of the pharmacological, pharmaceutical, technical, preclinical, and clinical experimental aspects of novel inhalation therapy for treating PF and focus on therapeutic methods that significantly improve existing technologies or expand the range of drugs that can be administered via inhalation. Although inhalation therapy for PF has some limitations, the advantages are significant, and further research and innovation about new inhalation techniques and drugs are encouraged.

The senescence of alveolar epithelial cells (AECs) and fibroblasts plays a pivotal role in the pathogenesis of idiopathic pulmonary fibrosis (IPF), a condition lacking specific therapeutic interventions. Curculigoside (CCG), a prominent bioactive constituent of Curculigo, exhibits anti-osteoporotic and antioxidant activities. Our investigation aimed to elucidate the anti-senescence and anti-fibrotic effects of CCG in experimental pulmonary fibrosis and delineate its underlying molecular mechanisms. Our findings demonstrate that CCG attenuates bleomycin-induced pulmonary fibrosis and lung senescence in murine models, concomitantly ameliorating lung function impairment. Immunofluorescence staining for senescence marker p21, alongside SPC or α-SMA, suggested that CCG's mitigation of lung senescence correlates closely with the deceleration of senescence in AECs and fibroblasts. In vitro, CCG mitigated H2O2-induced senescence in AECs and the natural senescence of primary mouse fibroblasts. Mechanistically, CCG can upregulate SIRT1 expression, downregulating P300 expression, enhancing Trim72 expression to facilitate P300 ubiquitination and degradation, reducing the acetylation levels of antioxidant enzymes, and upregulating their expression levels. These actions collectively inhibited endoplasmic reticulum stress (ERS) and alleviated senescence. Furthermore, the anti-senescence effects and mechanisms of CCG were validated in a D-galactose (D-gal)-induced progeroid model. This study provides novel insights into the mechanisms underlying the action of CCG in cellular senescence and chronic diseases, offering potential avenues for the development of innovative drugs or therapeutic strategies.

Age-related macular degeneration (AMD) is a major cause of blindness in the elderly worldwide. Multiple studies have shown that epithelial-mesenchymal transition (EMT) plays a pivotal role in the pathogenesis of AMD. Isorhamnetin (Isor) is a flavonoid compound that inhibits EMT in tumor cells. However, whether it can also attenuate EMT in the retinal pigment epithelium (RPE) is unknown. Therefore, our study was designed to probe the possible impact of Isor on EMT process in both mouse retina and ARPE-19 cells. C57BL/6 mice were utilized to establish a dry AMD model. Isor and LCZ (a mixture of luteine/β-carotene/zinc gluconate) were administered orally for 3 months. The effects of Isor on the retina were evaluated using fundus autofluorescence, optical coherence tomography, and transmission electron microscopy. Transwell and wound healing assay were employed to assess ARPE-19 cell migration. Western blotting and immunofluorescence were used to measure the protein expressions associated with EMT, Nrf2 and AKT/GSK-3β pathway. The findings indicated that Isor alleviated dry AMD-like pathological changes in vehicle mice retina, inhibited the migration of Ox-LDL-treated ARPE-19 cells, and repressed the EMT processes in vivo and in vitro. Furthermore, Isor activated Nrf2 pathway and deactivated AKT/GSK-3β pathway in both vehicle mice and ARPE-19 cells. Interestingly, when Nrf2 siRNA was transfected into ARPE-19 cells, the inhibitory effect of Isor on EMT and AKT/GSK-3β pathway was attenuated. These results suggested that Isor inhibited EMT processes via Nrf2-dependent AKT/GSK-3β pathway and is a promising candidate for dry AMD treatment.

Increased production of extracellular matrix is a necessary response to tissue damage and stress. In a normal healing process, the increase in extracellular matrix is transient. In some instances; however, the increase in extracellular matrix can persist as fibrosis, leading to deleterious alterations in organ structure, biomechanical properties, and function. Indeed, fibrosis is now appreciated to be an important cause of mortality and morbidity. Extensive research has illustrated that fibrosis can be slowed, arrested or even reversed; however, few drugs have been approved specifically for anti-fibrotic treatment. This is in part due to the complex pathways responsible for fibrogenesis and the undesirable side effects of drugs targeting these pathways. Natural products have been utilized for thousands of years as a major component of traditional medicine and currently account for almost one-third of drugs used clinically worldwide. A variety of plant-derived compounds have been demonstrated to have preventative or even reversal effects on fibrosis. This review will discuss the effects and the underlying mechanisms of some of the major plant-derived compounds that have been identified to impact fibrosis.

Age-related macular degeneration (AMD) is one of the common diseases that cause vision loss in the elderly, and oxidative stress has been considered a major pathogenic factor for AMD. Modified Danggui Buxue Decoction (RRP) has a good therapeutic effect on non-proliferatic diabetic retinopathy and can improve the clinical symptoms of patients.

The key ingredients and core targets of RRP protecting retinal oxidative damage were obtained by Network pharmacology analysis. A mouse retinal oxidative damage model induced by tail vein injection of 1% NaIO3 solution (25 mg/kg) was treated with RRP for 4 weeks and used to verify the pharmacodynamics and related mechanism.

This study aimed to predict and verify the protective effect and mechanism of RRP on retinal oxidative damage in mice based on network pharmacology and animal experiments.

A total of 15 key active components included in RRP interacted with 57 core targets related to retinal oxidative damage (such as AKT1, NFE2L2, HMOX1), mainly involved in the AGE-RAGE signaling pathway in diabetic complications, PI3K-AKT signaling pathway and so on. Further studies in vivo found that RRP improved the retinal oxidative damage, increased the content of SOD and GSH, decreased the content of MDA in mouse serum, promoted the expression of p-PI3K, p-AKT, Nrf2, HO-1 and NQO1 proteins in the mouse retina, and inhibited the expression of Nrf2 in the cytoplasm.

This study revealed that RRP had a protective effect on oxidative damage of the retina in mice, and might exert anti-oxidative effect by activating the PI3K/Akt/Nrf2 signal pathway. This study provided scientific data for the further development of hospital preparations of RRP, and a good theoretical basis for the clinical application of RRP.

Tissue transglutaminase (TG2) is a widely distributed multifunctional protein involved in a broad range of cellular and metabolic functions carried out in a variety of cellular compartments. In addition to transamidation, TG2 also functions as a Gα signaling protein, a protein disulfide isomerase (PDI), a protein kinase, and a scaffolding protein. In the nucleus, TG2 modifies histones and transcription factors. The PDI function catalyzes the trimerization and activation of heat shock factor-1 in the nucleus and regulates the oxidation state of several mitochondrial complexes. Cytosolic TG2 modifies proteins by the addition of serotonin or other primary amines and in this way affects cell signaling. Modification of protein-bound glutamines reduces ubiquitin-dependent proteasomal degradation. At the cell membrane, TG2 is associated with G protein-coupled receptors (GPCRs), where it functions in transmembrane signaling. TG2 is also found in the extracellular space, where it functions in protein cross-linking and extracellular matrix stabilization. Of particular importance in transglutaminase research are recent findings concerning the role of TG2 in gene expression, protein homeostasis, cell signaling, autoimmunity, inflammation, and hypoxia. Thus, TG2 performs a multitude of functions in multiple cellular compartments, making it one of the most versatile cellular proteins. Additional evidence links TG2 with multiple human diseases including preeclampsia, hypertension, cardiovascular disease, organ fibrosis, cancer, neurodegenerative diseases, and celiac disease. In conclusion, TG2 provides a multifunctional and multisite response to physiological stress.

Skeletal muscle atrophy is a common muscle disease that is directly caused by an imbalance in protein synthesis and degradation. At the histological level, it is mainly characterized by a reduction in muscle mass and fiber cross-sectional area (CSA). Patients with skeletal muscle atrophy present with reduced motor ability, easy fatigue, and poor life quality. Heme oxygenase-1 (HO-1) is an inducible enzyme that catalyzes the degradation of heme and has attracted much attention for its anti-oxidation effects. In addition, there is growing evidence that HO-1 plays an important role in anti-inflammatory, anti-apoptosis, pro-angiogenesis, and maintaining skeletal muscle homeostasis, making it a potential therapeutic target for improving skeletal muscle atrophy. Here, we review the pathogenesis of skeletal muscle atrophy, the biology of HO-1 and its regulation, and the biological function of HO-1 in skeletal muscle homeostasis, with a specific focus on the role of HO-1 in skeletal muscle atrophy, aiming to observe the therapeutic potential of HO-1 for skeletal muscle atrophy.