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Journal of Controlled Release :... Jun 2024Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and life-threatening lung disease for which treatment options are limited. Glycyrrhetinic acid (GA) is a...
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and life-threatening lung disease for which treatment options are limited. Glycyrrhetinic acid (GA) is a triterpenoid with multiple biological effects, such as anti-inflammatory and anti-fibrotic properties. Herein, inhalable milk-derived extracellular vesicles (mEVs) encapsulating GA (mEVs@GA) were screened and evaluated for IPF treatment. The results indicated that the loading efficiency of GA in mEVs@GA was 8.65%. Therapeutic effects of inhalable mEVs@GA were investigated in vitro and in vivo. The mEVs@GA demonstrated superior anti-inflammatory effects on LPS-stimulated MHS cells. Furthermore, repeated noninvasive inhalation delivery of mEVs@GA in bleomycin-induced IPF mice could decrease the levels of transforming growth factors β1 (TGF-β1), Smad3 and inflammatory cytokines IL-6, IL-1β and TNF-α. The mEVs@GA effectively diminished the development of fibrosis and improved pulmonary function in the IPF mice model at a quarter of the dose compared with the pirfenidone oral administration group. Additionally, compared to pirfenidone-loaded mEVs, mEVs@GA demonstrated superior efficacy at the same drug concentration in the pharmacodynamic study. Overall, inhaled mEVs@GA have the potential to serve as an effective therapeutic option in the treatment of IPF.
Topics: Animals; Glycyrrhetinic Acid; Idiopathic Pulmonary Fibrosis; Extracellular Vesicles; Administration, Inhalation; Milk; Mice, Inbred C57BL; Cytokines; Anti-Inflammatory Agents; Bleomycin; Male; Lung; Mice; Humans; Cell Line; Drug Carriers; Smad3 Protein
PubMed: 38754632
DOI: 10.1016/j.jconrel.2024.05.024 -
Scientific Reports May 2024This study aimed to investigate the potential anti-fibrotic activity of vinpocetine in an experimental model of pulmonary fibrosis by bleomycin and in the MRC-5 cell...
This study aimed to investigate the potential anti-fibrotic activity of vinpocetine in an experimental model of pulmonary fibrosis by bleomycin and in the MRC-5 cell line. Pulmonary fibrosis was induced in BALB/c mice by oropharyngeal aspiration of a single dose of bleomycin (5 mg/kg). The remaining induced animals received a daily dose of pirfenidone (as a standard anti-fibrotic drug) (300 mg/kg/PO) and vinpocetine (20 mg/kg/PO) on day 7 of the induction till the end of the experiment (day 21). The results of the experiment revealed that vinpocetine managed to alleviate the fibrotic endpoints by statistically improving (P ≤ 0.05) the weight index, histopathological score, reduced expression of fibrotic-related proteins in immune-stained lung sections, as well as fibrotic markers measured in serum samples. It also alleviated tissue levels of oxidative stress and inflammatory and pro-fibrotic mediators significantly elevated in bleomycin-only induced animals (P ≤ 0.05). Vinpocetine managed to express a remarkable attenuating effect in pulmonary fibrosis both in vivo and in vitro either directly by interfering with the classical TGF-β1/Smad2/3 signaling pathway or indirectly by upregulating the expression of Nrf2 enhancing the antioxidant system, activating PPAR-γ and downregulating the NLRP3/NF-κB pathway making it a candidate for further clinical investigation in cases of pulmonary fibrosis.
Topics: Animals; Vinca Alkaloids; Pulmonary Fibrosis; Transforming Growth Factor beta1; PPAR gamma; Mice; NF-kappa B; Smad3 Protein; Smad2 Protein; NLR Family, Pyrin Domain-Containing 3 Protein; Signal Transduction; Mice, Inbred BALB C; Alveolar Epithelial Cells; Humans; Bleomycin; Disease Models, Animal; Male; Cell Line; Oxidative Stress
PubMed: 38750140
DOI: 10.1038/s41598-024-61269-y -
Basic & Clinical Pharmacology &... Jul 2024This study investigated the therapeutic benefits of para-hydroxycinnamic acid in mice with bleomycin-induced lung fibrosis. Forty male BALB/c mice were randomly assigned...
This study investigated the therapeutic benefits of para-hydroxycinnamic acid in mice with bleomycin-induced lung fibrosis. Forty male BALB/c mice were randomly assigned to four groups: normal, which received 0.9% normal saline; induced, which received a single dose of bleomycin (5 mg/kg) by oropharyngeal challenge; pirfenidone-treated; and para-hydroxycinnamic acid-treated, which challenged with bleomycin and received a daily oral dose of 300 and 50 mg/kg, respectively, from day 7 to day 21. Tissue pro-fibrotic and inflammatory cytokines, oxidative indicators, pulmonary histopathology, immunohistochemistry of fibrotic proteins and the assessment of gene expression by RT-qPCR were evaluated on day 22 after euthanizing animals. Pirfenidone and para-hydroxycinnamic acid managed to alleviate the fibrotic endpoints by statistically improving the weight index, histopathological score and reduced expression of fibrotic-related proteins in immune-stained lung sections, as well as fibrotic markers measured in serum samples. They also managed to alleviate tissue levels of oxidative stress and inflammatory and pro-fibrotic mediators. para-Hydroxycinnamic acid enhanced the expression of crucial genes associated with oxidative stress, inflammation and fibrosis in vivo. para-Hydroxycinnamic acid has demonstrated similar effectiveness to pirfenidone, suggesting it could be a promising treatment for fibrotic lung conditions by inhibiting the TGF-β1/Smad3 pathway or through its anti-inflammatory and antioxidant properties.
Topics: Animals; Bleomycin; Pulmonary Fibrosis; Male; Oxidative Stress; Mice, Inbred BALB C; Mice; Coumaric Acids; Lung; Pyridones; Inflammation; Cytokines; Disease Models, Animal; Antioxidants; Transforming Growth Factor beta1
PubMed: 38745367
DOI: 10.1111/bcpt.14018 -
Pakistan Journal of Pharmaceutical... Jan 2024Nephrin is a transmembrane protein that maintains the slit diaphragm of renal podocyte. In chronic kidney disease (CKD), podocyte effacement causes damage to glomerular...
Nephrin is a transmembrane protein that maintains the slit diaphragm of renal podocyte. In chronic kidney disease (CKD), podocyte effacement causes damage to glomerular basement membrane barrier leading to proteinuria. Boerhavia diffusa, (BD), an Ayurveda herb, is used in treatment of various diseases particularly in relation to the urinary system. This study attempts to evaluate the effect of ethanolic extract of BD on the expression of nephrin in adenine induced CKD rats. CKD was induced in Wistar albino rats using adenine (600/mg/kg, orally for 10 days). CKD rats were treated with BD (400/mg/kg) and pirfenidone (500/mg/kg) orally for 14 days. The kidneys were harvested from euthanized animals and processed for histopathology, electron microscopy and immunohistochemistry, gene and protein expression of nephrin. Diseased rats treated with BD and pirfenidone showed reduction in the thickening of renal basement membranes and reduced haziness in brush border of PCT and glomeruli. Nephrin gene and protein expressions were higher in BD and pirfenidone treated group when compared to the disease control group. The structural and functional damage brought on by adenine-induced nephrotoxicity was countered by protective action of BD by up regulating the expression of nephrin. Therefore, BD can be utilized as a nutraceutical for the prevention and treatment of CKD.
Topics: Animals; Membrane Proteins; Rats, Wistar; Podocytes; Plant Extracts; Adenine; Renal Insufficiency, Chronic; Male; Rats; Disease Models, Animal
PubMed: 38741412
DOI: No ID Found -
Frontiers in Immunology 2024Growing evidence from animal models indicates that the myocardium hosts a population of B cells that play a role in the development of cardiomyopathy. However, there is...
INTRODUCTION
Growing evidence from animal models indicates that the myocardium hosts a population of B cells that play a role in the development of cardiomyopathy. However, there is minimal data on human myocardial B cells in the context of cardiomyopathy.
METHODS
We integrated single-cell and single-nuclei datasets from 45 healthy human hearts, 70 hearts with dilated cardiomyopathy (DCM), and 8 hearts with arrhythmogenic right ventricular cardiomyopathy (ARVC). Interactions between B cells and other cell types were investigated using the CellChat Package. Differential gene expression analysis comparing B cells across conditions was performed using DESeq2. Pathway analysis was performed using Ingenuity, KEGG, and GO pathways analysis.
RESULTS
We identified 1,100 B cells, including naive B cells and plasma cells. Cells showed an extensive network of interactions within the healthy myocardium that included outgoing signaling to macrophages, T cells, endothelial cells, and pericytes, and incoming signaling from endothelial cells, pericytes, and fibroblasts. This niche relied on ECM-receptor, contact, and paracrine interactions; and changed significantly in the context of cardiomyopathy, displaying disease-specific features. Differential gene expression analysis showed that in the context of DCM both naive and plasma B cells upregulated several pathways related to immune activation, including upregulation of oxidative phosphorylation, upregulation of leukocyte extravasation, and, in naive B cells, antigen presentation.
DISCUSSION
The human myocardium contains naive B cells and plasma cells, integrated into a diverse and dynamic niche that has distinctive features in healthy, DCM, and ARVC. Naive myocardial-associated B cells likely contribute to the pathogenesis of human DCM.
Topics: Humans; Cardiomyopathy, Dilated; Arrhythmogenic Right Ventricular Dysplasia; B-Lymphocytes; Myocardium; Male; Female; Cell Communication; Gene Expression Profiling; Middle Aged; Adult; Transcriptome; Gene Expression Regulation
PubMed: 38736889
DOI: 10.3389/fimmu.2024.1327372 -
Journal of Clinical Medicine May 2024: Pirfenidone and Nintedanib have significantly improved the prognosis of patients with idiopathic pulmonary fibrosis (IPF), reducing mortality risk and exacerbations....
: Pirfenidone and Nintedanib have significantly improved the prognosis of patients with idiopathic pulmonary fibrosis (IPF), reducing mortality risk and exacerbations. This study aimed to analyze antifibrotic treatment utilization and its association with clinical outcomes (i.e., acute exacerbation or death) during 2014-2021 in newly diagnosed IPF patients, using Healthcare Utilization Databases of the Marche Region, Italy. : The first 12-month adherence to antifibrotic was estimated using the Proportion of Days Covered (PDC), defining adherence as PDC ≥ 75%. State Sequence Analysis over the initial 52 weeks of treatment was used to identify adherence patterns. The role of adherence patterns on acute exacerbations/death, adjusted by demographic, clinical features, and monthly adherence after the 52-week period (time-dependent variable), was assessed with Cox regression. : Among 667 new IPF cases, 296 received antifibrotic prescriptions, with 62.8% being adherent in the first year. Three antifibrotic utilization patterns emerged-high adherence (37.2%), medium adherence (42.5%), and low adherence (20.3%)-with median PDCs of 95.3%, 79.5%, and 18.6%, respectively. These patterns did not directly influence three-year mortality/exacerbation probability, but sustained adherence reduced risk over time. : Good adherence was observed in in this population-based study, emphasizing the importance of continuous antifibrotics therapy over time to mitigate adverse outcomes.
PubMed: 38731256
DOI: 10.3390/jcm13092727 -
Therapeutic Drug Monitoring May 2024Mutations in metabolic enzymes and co-administration of drugs may affect the blood concentration of pirfenidone effective in pulmonary fibrosis. To provide a basis for...
BACKGROUND
Mutations in metabolic enzymes and co-administration of drugs may affect the blood concentration of pirfenidone effective in pulmonary fibrosis. To provide a basis for the precise clinical use of pirfenidone, the authors analyzed the correlation between steady-state pirfenidone trough concentration and adverse drug reactions (ADRs) and examined the impact of CYP1A2*1C (rs2069514) and *1F (rs762551) variants and co-administration on pirfenidone blood concentrations and ADRs.
METHODS
Forty-four patients were enrolled. The blood concentration of pirfenidone was determined using high-performance liquid chromatography. CYP1A2*1C and *1F genotypes were determined using direct SNP sequencing. Additional information related to drug associations was collected to screen factors affecting drug metabolism.
RESULTS
The highest predictive value of ADRs was observed when the steady-state trough concentration of pirfenidone was 3.18 mcg·mL-1 and the area under the receiver operating characteristic curve was 0.701 (P = 0.024). The pirfenidone concentration-to-dose ratio (C/D) in CYP1A2*1F homozygous AA mutants was lower than that in C carriers (CC+AC) (1.28 ± 0.85 vs. 2.03 ± 1.28 mcg·mL-1; P = 0.036). Adverse drug reaction (ADR) incidence in the homozygous AA mutant group (28.0%) was significantly lower than that in the C carriers (CC+AC) (63.2%; P = 0.020), and ADR incidence in the A carriers (AC+AA) was considerably lower than that in the CC group (85.7%; P = 0.039). The C/D value of the combined lansoprazole/rabeprazole group was lower than that of the noncombination group (P < 0.05).
CONCLUSIONS
The ADR incidence was positively correlated with pirfenidone blood concentration. The CYP1A2 (rs762551) AA genotype is associated with lower pirfenidone concentrations and fewer ADRs. Lansoprazole/rabeprazole co-administration reduced pirfenidone concentrations. Randomized controlled trials should further explore personalized dosing of pirfenidone and combination therapies.
PubMed: 38723157
DOI: 10.1097/FTD.0000000000001208 -
Internal Medicine (Tokyo, Japan) May 2024Herein, we report a case of Hermansky-Pudlak syndrome (HPS) in which respiratory symptoms improved with pirfenidone treatment. A 43-year-old Japanese woman with...
Herein, we report a case of Hermansky-Pudlak syndrome (HPS) in which respiratory symptoms improved with pirfenidone treatment. A 43-year-old Japanese woman with oculocutaneous albinism presented with a cough and dyspnea. High-resolution computed tomography revealed areas of reticular and frosted lung opacities. The diagnosis of HPS was confirmed by a prolonged bleeding time and HPS1 gene mutation. Generally, there is no effective treatment for interstitial pneumonia associated with HPS except for lung transplantation. In the present case, the cough and dyspnea improved with pirfenidone administration. Therefore, clinicians should administer pirfenidone in challenging transplantation cases and during the waiting period for transplantation.
PubMed: 38719600
DOI: 10.2169/internalmedicine.3459-24 -
Nan Fang Yi Ke Da Xue Xue Bao = Journal... Apr 2024To observe the effect of (SQCC) Formula on the ASS1/src/STAT3 signaling pathway in a rat model of lung fibrosis and explore its therapeutic mechanism.
OBJECTIVE
To observe the effect of (SQCC) Formula on the ASS1/src/STAT3 signaling pathway in a rat model of lung fibrosis and explore its therapeutic mechanism.
METHODS
A total of 120 male SD rats were divided equally into 5 groups, including a blank control group with saline treatment and 4 groups of rat models of idiopathic pulmonary fibrosis induced by intratracheal instillation of bleomycin. One day after modeling, the rat models were treated with daily gavage of 10 mL/kg saline, SQCC decoction (0.423 g/kg), pirfenidone (10 mL/kg), or intraperitoneal injection of arginine deiminase (ADI; 2.25 mg/kg, every 3 days) for 28 days. After the treatments, the lung tissues of the rats were collected for calculating the lung/body weight ratio, observing histopathology using HE and Masson staining, and analyzing the inflammatory cells in BALF using Giemsa staining. Serum chemokine ligand 2 (CCL2) and transforming growth factor-β1 (TGF-β1) levels were measured with ELISA. The protein expressions of src, p-src, STAT3, and p-STAT3 and the mRNA expressions of ASS1, src and STAT3 in the lung tissues were detected using Western blotting and RT-qPCR.
RESULTS
The neutrophil, macrophage and lymphocyte counts and serum levels of CCL2 and TGF-β1 were significantly lower in SQCC, pirfenidone and ADI treatment groups than in the model group at each time point of measurement ( < 0.05). P-src and p-STAT3 protein expression levels and ASS1, src, and STAT3 mRNA in the lung tissues were also significantly lower in the 3 treatment groups than in the model group ( < 0.05).
CONCLUSION
SQCC Formula can alleviate lung fibrosis in rats possibly by activating the ASS1/src/STAT3 signaling pathway in the lung tissues.
Topics: Animals; Male; Rats; Bleomycin; Chemokine CCL2; Disease Models, Animal; Drugs, Chinese Herbal; Inflammation; Lung; Pulmonary Fibrosis; Rats, Sprague-Dawley; Signal Transduction; src-Family Kinases; STAT3 Transcription Factor; Transforming Growth Factor beta1; Carbon-Carbon Ligases
PubMed: 38708496
DOI: 10.12122/j.issn.1673-4254.2024.04.04 -
European Journal of Pharmaceutical... Jul 2024Transforming growth factor-beta1 (TGF-β1) plays a pivotal role in promoting hepatic fibrosis, pirfenidone (PFD) could inhibit TGF-β1 signaling pathway to alleviate...
RATIONALE
Transforming growth factor-beta1 (TGF-β1) plays a pivotal role in promoting hepatic fibrosis, pirfenidone (PFD) could inhibit TGF-β1 signaling pathway to alleviate hepatic stellate cells (HSC) activation mediated hepatic fibrosis. The targeting delivery strategy of PFD to hepatic stellate cells is a challenge. Extracellular vesicles (EVs), cell-derived membranous particles are intraluminal nano-vesicles that play a vital role in intercellular communication, they also be considered as an ideal nano-carrier.
METHODS
In this study, we developed a target strategy to deliver PFD to HSC with CD44 over-expression by EVs, hyaluronic acid (HA) modified DSPE-PEG endows the active targeting ability of activated HSCs to PFD-loaded EVs.
RESULTS
In both rat hepatic stellate cell line HSC-T6 and rat hepatocyte cell line BRL, HA@EVs-PFD demonstrated the capacity to down-regulate the expression of collagen-synthesis-related proteins and showed superior inhibition efficacy of HSC-T6 activation compared to free PFD. In hepatic fibrosis model, 4 weeks of HA@EVs-PFD treatment resulted in a reduction in liver collagen fibers, significant improvement in hepatic cell morphology, and amelioration of hepatic fibrosis.
CONCLUSIONS
HA@EVs-PFD, as a drug delivery system that effectively targets and inhibits activated HSCs to treat hepatic fibrosis, holds promise as a potential therapeutic agent against hepatic fibrosis.
Topics: Hepatic Stellate Cells; Animals; Hyaluronic Acid; Extracellular Vesicles; Liver Cirrhosis; Rats; Cell Line; Male; Pyridones; Transforming Growth Factor beta1; Rats, Sprague-Dawley
PubMed: 38703918
DOI: 10.1016/j.ejps.2024.106783