Clearance reflects the speed of extraction and elimination of drug molecules from systemic circulation. Reducing the clearance of compounds using structure modification strategy could lead to good pharmacokinetic and pharmacodynamic properties. Herein, the concept of clearance, as well as several prediction methods of in vivo clearance are introduced. The strategies of reducing drug clearance are reviewed. These methods include reducing hepatic metabolic clearance through reducing lipophilicity, blocking metabolic site, scaffold modification and increasing steric hindrance; reducing biliary or renal excretion clearance through increasing lipophilicity, reducing polar surface area and bioisosterism. In addition, the influence of spatial configuration on drug clearance is also summarized.

Polymeric micelles have become a potential drug carrier. However, some single-copolymer micelles often have some performance defects, such as low drug loading, poor stability and weak response to microenvironment. Mixed micelles self-assembled from two or more dissimilar macromolecular polymers provides a direct and convenient approach to improve drug delivery. This paper attempts to review the internal force, preparation and characterization, performance advantages and biological activity of mixed polymer micelles, aims to show the advantages of polymer mixed micelles, analyzes the problems and shortcomings, and hopes to provide reference for the development of anti-tumor nano-micelles.

Idiopathic pulmonary fibrosis (IPF) is an irreversible and highly mortal interstitial disease. The incidence of IPF is increasing around the world, which seriously harms human health and brings huge economic burden to the society. While traditional treatments can slow the progression of the disease, they are far to cure this disease. Clinically, pirfenidone and nintedanib are two main drugs that used for the treatment of IPF. However, severe adverse reactions were reported in some patients. Therefore, it is very important to explore novel therapeutic strategies to reverse fibrosis and regenerate lung. The repair and regeneration ability of stem cells has unique advantages in the treatment of pulmonary fibrosis. The structure and function of organoids produced by stem cells have similar characteristics with live organs. Therefore, lung stem cells play an important role in the discovery of novel anti-IPF drugs, and in the formation and development of lung tissue. In addition, organoids produced by stem cells also serve as a perfect model for regenerative medicine. In this review, we mainly summarize the role of stem cells and organoids in the repair and regeneration of pulmonary fibrosis, and hope to provide a reference for the development of clinical treatment of pulmonary fibrosis.

Idiopathic pulmonary fibrosis is a fibrous disease. At present, its pathogenesis has not been fully elucidated and there is no drug with definite therapeutic effect. After four stages of development, antibody drugs are becoming a new hotspot in drug research and development with their own advantages. A number of drugs have entered the stage of clinical trials. Based on this, this review summarizes the antibody drugs for the clinical stage of clinical research of idiopathic pulmonary fibrosis, in order to summarize the development of antibody drugs, and provide certain bases and ideas for the development of antibody drugs.

We investigated the therapeutic effect and mechanism of isoforskolin on bleomycin-induced pulmonary fibrosis in mice. The animal welfare and experimental process were in accordance with the Regulations of Animal Ethics Committee of Kunming Medical University. Male Kunming mice were randomly divided into five groups: sham operation group (intratracheal instillation of normal saline), bleomycin group (intratracheal instillation of bleomycin 5 mg·kg^-1), positive drug control group (intratracheal instillation of bleomycin 5 mg·kg^-1 + intraperitoneal injection of dexamethasone sodium phosphate 2.5 mg·kg^-1), isoforskolin (2.5 and 10 mg·kg^-1) groups (intratracheal instillation of bleomycin 5 mg·kg^-1 + intragastric administration of isoforskolin 2.5 and 10 mg·kg^-1). The method of drug administration was once a day for 28 days. On the 7^th and 28^th day of the experiment, the mice were killed, and the lung tissue and bronchoalveolar lavage fluid samples were collected. Hematoxylin eosin (H & E) staining and Masson staining were used to detect the pathological changes of lung tissue. The content of hydroxyproline in lung tissue was detected by alkaline hydrolysis method. The levels of tumor necrosis factor α (TNF-α) and interleukin 1β (IL-1β) in bronchoalveolar lavage fluid (BALF) were detected by enzyme linked immunosorbent assay (ELISA). The expressions of transforming growth factor β1 (TGF-β1) and connective tissue growth factor (CTGF) in lung tissue were detected by Western blot. The experimental results showed that compared with the bleomycin group, the degree of inflammation and fibrosis in the lung tissue of mice in 10 mg·kg^-1 isoforskolin group was significantly reduced, the content of hydroxyproline in the lung tissue was decreased, the levels of TNF-α and IL-1β in BALF were decreased, and the protein expressions of TGF-β1 and CTGF in the lung tissue were downregulated, the differences were statistically significant (P < 0.05). The results suggest that isoforskolin can inhibit the release of inflammatory cytokines TNF-α and IL-1β, downregulate the protein expression of profibrotic factors TGF-β1 and CTGF, and exert anti pulmonary fibrosis effect through both anti-inflammatory and anti fibrotic effect.

The mechanism of Platycodon grandiflorum in the treatment of pulmonary fibrosis was examined by integrated pharmacology network with animal experiment validation. Compositions and targets of Platycodon grandiflorum were collected utilizing databases such as TCMSP and Swiss Target Prediction, whereas pulmonary fibrosis targets were obtained using GeneCards, OMIM, Disgenet, and Drugbank databases. These datasets were merged in order to identify prospective Platycodon grandiflorum targets for the treatment of pulmonary fibrosis. The "drug-component-target-disease" network was constructed with Cytoscape software, and the interaction relationship between potential targets was produced; they were coupled with the String platform to create the PPI network while also doing topological analysis. Then, using R software and the Bioconductor biological information software package, we conduct GO and KEGG enrichment analysis to estimate the therapeutic mechanism. A mouse model of pulmonary fibrosis was constructed for pathological staining, ELISA, lung function, qRT-PCR, and Western blot to validate the results of the network pharmacology. There are 289 putative active components of Platycodon grandiflorum, and 1 129 disease targets for pulmonary fibrosis, for a total of 65 drug-compound-disease common targets. The GO enrichment analysis revealed 1 575 items, whereas the KEGG enrichment analysis yielded 146 entries. The phosphatidylinositol 3 kinase-protein kinase B (PI3K-AKT) signaling pathway, the tumor necrosis factor (TNF) signaling system, and the interleukin-17 (IL-17) signaling pathway were enriched. In animal experiments, Platycodon grandiflorum was found to decrease lung inflammation and collagen deposition in mice with pulmonary fibrosis. According to Western blot results, the expression of PI3K-AKT signaling pathway-related proteins p-PI3K and p-AKT was down-regulated in a dose-dependent manner after Platycodon grandiflorum therapy of pulmonary fibrosis mice. When p-AKT was suppressed, P21 expression was reduced, indicating that Platycodon grandiflorum may control the expression of PI3K-AKT pathway-related proteins to alter cell senescence while treating mice with pulmonary fibrosis. This study uses network pharmacology to identify the targets and pathways of Platycodon grandiflorum against pulmonary fibrosis and conducts related animal experimental validation, providing a foundation for an in-depth discussion of the therapeutic mechanism of Platycodon grandiflorum against pulmonary fibrosis.

Pulmonary fibrosis (PF) is a chronic respiratory inflammation disease that threatens human health. The topical immune microenvironment of lung tissue regulates progression of fibrosis. In this study, the efficacy and molecular mechanism of suplatast tosilate (ST) against PF were observed. ST is a T helper 2 (Th2) cytokine inhibitor for clinical treatment of bronchial asthma. But whether it can be applied to therapy of chronic PF and the biomechanism of ST inhibiting Th2 cytokine release are not clear. Using in vivo and in vitro experiments, we found that ST can significantly suppress the pathogenesis of chronic PF induced by multiple bleomycin injury, improve the lung function, and decrease the deposition of collagen in lung tissue. In addition, ST decreases Th2 cytokine releasing through restraining Th2 cell differentiation in the meantime, but did not influence the T helper 1 (Th1) cell differentiation and Th1 cytokine releasing. Further studies showed that ST inhibits Th2 cell differentiation by down-regulating GATA-binding protein 3 (GATA3) expression and activity through inhibiting the phosphorylation of signal transducer and activator of transcription 5 (STAT5) and mammalian target of rapamycin (mTOR). The excessive expression of GATA3 in lungs can reverse the anti-PF effect of ST. All procedures involving animal treatment were approved according to the Committee on the Ethics of Animal Experiments of the Institute of Materia Medica, Chinese Academy of Medical Sciences. Our research not only clarifies the pharmacological mechanism of ST, but also provides a new selection for clinical anti-PF drug therapy.

Glycosylation abnormalities are common in all stages of tumor development, and sialic acid (SA) modified polysaccharides have been found highly expressed on many different types of tumor cells. These highly sialylated tumor cells promote the formation of tumor immunosuppressive environment and help tumor cells gain metastatic potential by interacting with SA binding receptors Siglecs/selectins expressed on peripheral immune cells or endothelial cells. Related theoretical studies have promoted the development of tumor therapeutic strategies by targeting SA-binding receptors, mainly including specific antibodies trastuzumab (Mylotarg) or polysaccharides that block the interaction between Siglecs/selectins and its ligands, as well as nano-based drug delivery systems modified with SA and its derivatives. This article reviews the specific mechanisms of how SA-binding receptor Siglecs/selectins-mediated interactions contribute to tumor development and metastasis, and tumor therapeutic strategies by targeting SA-binding receptors, as well as makes a rational evaluation and reflection on these therapeutic strategies.

We aimed to explore the involvement of Fas-associated death domain protein (FADD) in the inhibitory effects of etoposide (VP16) on the proliferation, migration, and apoptosis of A549 non-small cell lung cancer (NSCLC) cells. FADD knockout (KO) and control A549 cells were constructed using the CRISPR/Cas9 system. The cell counting kit-8 (CCK-8) assay, the scratch wounding assay, and the Annexin V/PI staining-based flow cytometry were used to assess the effect of FADD KO on viability, migration, and apoptosis of A549 cells with or without the presence of etoposide, respectively. The expression pattern of several proteins involved in proliferation[raf proto-oncogene serine/threonine-protein kinase (c-Raf) and extracellular signal-regulated kinase of phosphorylation (p-ERK)], apoptosis[B-cell lymphoma 2 (BCL2), cleaved cysteinyl aspartate specific proteinase 3 (cleaved-caspase-3), and cleaved-caspase-9] and migration[matrix metalloproteinase 2 (MMP2)] was detected by Western blot. We found that FADD KO attenuated proliferation and migration of A549 cells. Consistently, we demonstrated that FADD KO enhanced etoposide-mediated inhibition of proliferation and migration in A549 cells. We further demonstrated that FADD KO obviously enhanced etoposide-mediated apoptosis in A549 cells. For mechanism exploration, we found that etoposide sensitivity enhanced by FADD KO may be partly explained by reduced expression of c-Raf, p-ERK, MMP2, and increased cleavage of caspase-3 and -9. Combined with the Kaplan-Meier (KM) survival curve analysis obtained from the GEPIA database, it is preliminarily judged that patients with high FADD gene levels in lung adenocarcinoma have a poor prognosis. Our study suggests that FADD can be used as a potential biomarker for the treatment of lung adenocarcinoma, providing a personalized treatment plan for the treatment of lung adenocarcinoma.

A simple and efficient method for extracting Cistanche polysaccharides was obtained and used to extract four Cistanche polysaccharides. The molecular weight, distribution and polysaccharide mass fraction of the four Cistanche polysaccharides were measured by High performance size exclusion chromatography-multiangle laser light scatter-refractive index detector (HPSEC-MALLS-RID) and differences between the four Cistanche polysaccharides were determined. The results of a single factor test and an orthogonal test showed that the best process parameters for extracting Cistanche polysaccharides used a mixture of enzyme (4%), a ratio of complex enzyme (cellulase∶pectinase) 1∶1, ultrasonic power at 350 W (40 kHz), for 20 min, enzymolysis temperature of 50 ℃, and pH 6. The average yield of three repeated extractions was 5.14%, the mass fraction was 90.78%, the comprehensive index was 47.96%, and the RSD = 1.51%, indicating good reproducibility. The four Bossica Cistanche polysaccharides are all spherical structures but their molecular weights and distributions differ. The optimized compounded enzyme combined with ultrasonic extraction increases the yield of Cistanche polysaccharides. It is a simple, convenient, economical and environmentally friendly extraction method, which lays the foundation for future polysaccharide research.