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.

Cardiac fibrosis is a vital pathological feature of various cardiovascular diseases, including myocardial infarction and heart failure. However, there have been few clinical interventions to treat cardiac fibrosis. Noncoding RNAs (ncRNAs) are a class of RNAs that do not encode proteins. ncRNAs participate in various cellular biological processes and regulate gene expression at transcription, post-transcription and epigenetic levels. Recent studies demonstrate that ncRNAs participate in the regulation of cardiac fibrosis by affecting the proliferation and transition of cardiac fibroblasts. ncRNAs can be used as potential intervention targets and biomarkers for cardiac fibrosis, provide new strategies and approach for treating and preventing fibrosis associated cardiovascular diseases. This review summarizes the function and mechanisms of ncRNAs in cardiac fibrosis.

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.

S-phase kinase-associated protein 2 (Skp2) is one of the components of E3 ubiquitin ligase, which can induce proteasome-mediated proteolysis or regulate labeled substrates to promote cell proliferation and migration and inhibit cell apoptosis and senescence by connecting the ubiquitin chains of K48 and K63 to different substrates. Skp2 is also a potential drug target in a variety of fibrotic diseases, is highly expressed in a variety of fibrotic diseases, and regulates the occurrence and progression of these diseases. This paper reviews Skp2's structure, downstream targets, and cellular regulation and then focuses on research progress on Skp2 in various fibrotic diseases, such as liver fibrosis, idiopathic pulmonary fibrosis, renal fibrosis, corneal fibrosis, and cardiac fibrosis, which may help provide a new research approaches for clinical development of Skp2-targeted antifibrotic drugs.

Liver fibrosis is a common pathological process that many chronic liver diseases must undergo to develop into cirrhosis and hepatocellular carcinoma. Liver fibrosis is regulated by a variety of cytokines and signal pathways during its occurrence and development. In recent years, a large number of studies showed that ferroptosis is closely related to liver fibrosis. Compared with normal liver, the levels of irons and lipid peroxidation in the liver with fibrosis are significantly increased. Therefore, ferroptosis may be a potential target for the diagnosis, prevention, and treatment of liver fibrosis. This review summarizes the role of ferroptosis in liver fibrosis, thus to provide new ideas for the treatment of liver fibrosis.

Fibrosis is a common manifestation of organ damage and failure. According to relevant statistics in the United States, deaths caused by fibrotic diseases account for 45% of all deaths in the country. Therefore, fibrotic diseases have received widespread attention worldwide. As a key kinase that regulates energy balance, AMP-activated protein kinase (AMPK), which mainly controls the transformation of cells from anabolic to catabolism, and restores the energy balance by phosphorylating its substrates. Therefore, it has become the core of treatment for diabetes and other metabolic-related diseases. Numerous recent pathological studies have shown that the expression of AMPK in fibrotic tissues is significantly down-regulated compared with normal tissues, and activation of AMPK could improve various fibrotic pathological processes (including autophagy dysfunction, oxidative stress, fibroblast proliferation, epithelial-mesenchymal transition, fibroblast-to-myofibroblast differentiation). Therefore, this review will discuss the structure and function of AMPK and its role in important phenotypes of fibrotic diseases, and provide evidence for AMPK as an important target for prevention and treatment of fibrosis.

Epithelial mesenchymal transition (EMT) is a reprogramming process of epithelial to mesenchymal transition, in which epithelial cells lose polarity and intercellular adhesion and acquire stronger migration and invasion ability similar to mesenchymal cells. EMT is a critical step during the pathogenesis of pulmonary fibrosis. Lung epithelial cells can differentiate into myofibroblasts through EMT, which accelerates the fibrosis process. In recent years, a large number of studies have shown that non-coding RNAs (ncRNAs) are involved in the EMT process of lung epithelial cells, at the same time, some natural medicines were found to prevent and treat pulmonary fibrosis by intervening in ncRNAs related to pulmonary fibrosis. In this review, we summarize the expression change and biological function of vital ncRNAs in EMT progression during pulmonary fibrosis, as well as the research progress of EMT related ncRNA mediated by natural medicines on pulmonary fibrosis, aiming to provide new insights into the research of ncRNAs and the exploration of new pharmacological targets of natural medicine.

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.

In this study, we investigated the effect and mechanism of glaucocalyxin A on transforming growth factor-β1 (TGF-β1)-induced differentiation of lung fibroblasts by Western blotting, cellular immunofluorescence and collagen gel contraction assays. We monitored the phosphorylation of Smad3, measured extracellular regulated protein kinases (ERK) 1/2 and glycogen synthase kinse3β (Ser9) activity and the level of β-catenin to elucidate the role of glaucocalyxin A. The results show that glaucocalyxin A significantly decreased the expression of α-smooth muscle actin in lung fibroblasts; glaucocalyxin A remarkably reduced the formation of filaments and collagen gel contraction of lung fibroblasts; glaucocalyxin A notably down-regulated the production of fibronectin; glaucocalyxin A did not affect the phosphorylation level of Smad3 and ERK1/2; glaucocalyxin A markedly inhibited the phosphorylation of GSK3β (Ser9) and the levels of β-catenin; a GSK3β (S9A) mutant significantly inhibited lung fibroblast differentiation; and SKL2001, a β-catenin activator, partly reversed the inhibition of lung fibroblast differentiation by glaucocalyxin A. These results suggest that glaucocalyxin A significantly inhibits the differentiation of lung fibroblasts, which is related to the down-regulation of GSK3β/β-catenin signaling.

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.

Chaihu Shugan San (CHSGS), a classic traditional Chinese medicinal formula, has been widely used in clinics for emotional disease. Here the protective effect and possible mechanisms of Chaihu Shugan San in stress-induced liver injury were investigated. The animal experimental protocol has been reviewed and approved by Laboratory Animal Ethics Committee of Jinan University, in compliance with the Institutional Animal Care Guidelines. Mice were administered CHSGS for 7 days and subjected to 18-h acute stress before being killed. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and malondialdehyde (MDA) levels in serum were measured with commercial kits. Histomorphology of the liver was analyzed by hematoxylin-eosin staining and immunohistochemistry. Glutathione (GSH) content, 4-hydroxynonenal (4-HNE), brain and muscle Arnt-like protein-1 (BMAL1) and arachidonate 15-lipoxygenase (ALOX15) protein were detected by LC-MS and Western blot, respectively. The results showed that CHSGS ameliorated acute stress-induced liver damage by reducing ALT and AST levels in serum and inflammatory infiltration in liver tissue. Network pharmacology analysis showed that CHSGS was associated with lipid peroxidation. Further analysis confirmed that MDA and 4-HNE levels declined and GSH level increased in livers of stressed mice after CHSGS administration. CHSGS also lowered BMAL1 expression, a pivotal factor in circadian rhythm, in livers of stressed mice. In conclusion, CHSGS ameliorated stress-induced liver injury by repressing lipid peroxidation and regulating circadian rhythm. Our studies implicate that CHSGS is promising as a therapy for stress-induced liver injury, and lay foundation for designing novel prophylactic and therapeutic strategies for stress-induced liver injury.

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.

Liver fibrosis is a common scarring response to virtually all forms of chronic liver injury and is characterized by excessive accumulation of extracellular matrix. Excessive activation of hepatic stellate cells (HSCs) is a key step in liver fibrogenesis. The withanolide extract of Physalis angulata (WEP) is a physalin-type withanolide enriched partition from Physalis angulata. In this study, liver fibrosis mice models were established by CCl₄ and bile duct ligation (BDL) in vivo. Transforming growth factor-β1 (TGF-β1) was given in vitro to induce activation of human hepatic stellate cells LX-2 and treated with WEP at different concentrations. All animal experiments in this paper have been approved by the Ethics Committee of China Pharmaceutical University. The in vivo results showed that, compared with the CCl₄ or BDL group, WEP could reduce collagen deposition and liver damage, and reduce the levels of aspartate transaminase (AST) and alanine transaminase (ALT) in serum. In vitro, WEP had no significant cytotoxicity to LX-2 cells, but significantly reduced the mRNA and protein expressions of fibrotic markers collagen type Ⅰ α 1 chain (COL1A1) and α-smooth muscle actin (α-SMA) and inhibited the activation of hepatic stellate cells. In addition, WEP inhibited the expression of yes-associated protein (YAP) and the phosphorylation level of Smad family member 2 (Smad2) in vivo and in vitro. In conclusion, WEP can inhibit hepatic stellate cells activation via regulating the YAP and TGF-β-Smad pathways, and shows promising anti-fibrosis activity in vitro and in vivo.

Hepatic fibrosis is a common pathological link of multiple chronic liver diseases, and further causes cirrhosis and even liver cancer. Tibetan medicine possessed significant and unique clinical effects in the prevention and treatment of hepatic fibrosis through unique medication methods such as single prescription, time synergy, and dialectical combination prescription. Pharmacological experimental studies have shown that a variety of Tibetan medicine formulas and herbs have anti-fibrotic effects, and their main pharmacological action mechanism involves inhibiting lipid peroxidation, reducing liver stellate cell activation and proliferation, regulating collagen metabolism, etc. This review summarizes the research progress of the clinical application and pharmacodynamic mechanism of Tibetan medicine in the prevention and treatment of liver fibrosis, aiming to provide a reference for the development of clinical use and innovative drugs discovery of Tibetan medicine against hepatic fibrosis.

With the increasing drug resistance of bacteria, especially Gram-negative bacteria, the infection of drug-resistant bacteria has become one of the most challengeable clinical problems. The siderophore-antibiotic conjugates based on the "Trojan horse" strategy can penetrate the extracellular membrane of Gram-negative bacteria by active transport, and they are expected to become a powerful weapon for clinical anti-infection treatment. This review describes the drug design strategies of siderophore-antibiotic conjugates reported in recent years, and focuses on the use of different types of antibiotics in this strategy.

The development of mass spectrometry and proteomics significantly advanced our understanding of post-translational methylation of proteins. In recent years, a large number of proteins containing the methylation recognition domain have been identified. Protein methylation mainly occurs on lysine and arginine residues. Both lysine and arginine have three different methylation states. Lysine can be mono-methylated, di-methylated, and tri-methylated, while the arginine residue can be modified as mono-methylation, symmetrical di-methylation, and asymmetrical di-methylation. Methylation recognition domains can accurately identify lysine or arginine with different state of methylation, transfer methylation signals, and perform functions in a variety of cellular processes, including gene expression regulation, RNA splicing and translation, cell cycle regulation, etc. In recent years, researchers have found that the abnormalities of these recognition proteins are also closely related to the genesis and development of tumors. Therefore, these methylation recognition proteins were considered as potential drug targets for small molecule intervention. In this review, we summarized the researches on the recognition domains of protein methylation as well as their inhibitors, hoping to provide the basis for further drug development in this field.

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.

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.

We analyzed the main chemical constituents of Huangqi decoction by HPLC coupled with diode array and evaporative light scattering detectors (HPLC-DAD-ELSD). The study on the mechanism of Huangqi decoction was based on network pharmacology and included multi-components, multi-targets, and multi-pathways in the treatment of non-alcoholic fatty liver disease (NAFLD). The chemical "fingerprints" of 15 batches of Huangqi decoction were established. Network pharmacology was used to screen and analyze the targets and pathways of the components of Huangqi decoction, and a "component-target-pathway" network was constructed to predict the mechanism of Huangqi decoction for the treatment of NAFLD. HPLC analysis of Huangqi decoction revealed 27 common peaks and the main chemical constituents were identified. Gene ontology (GO) analysis and Kyoto encyclopedia of genes and genomes (KEGG) pathway analysis revealed that glycyrrhetinic acid, isoliquiritigenin, glycyrrhizic acid, astragaloside Ⅳ, liquiritigenin, and astragaloside Ⅰ, the main active components of Huangqi decoction, may act on RAC-alpha serine/threonine-protein kinase (AKT1), interleukin-6 (IL-6), vascular endothelial cell growth factor A (VEGFA), mitogen-activated protein kinase 8 (MAPK8), and signal transducer and activator of transcription 3 (STAT3), and may regulate pathways involving phosphatidylinositol-3-kinases (PI3K)/protein kinase B (AKT), insulin resistance, hypoxia inducible factor-1 (HIF-1), tumor necrosis factor (TNF), among others. A decrease in insulin resistance, a reduction of inflammation, and anti-oxidative stress-related effects may be the mechanism of Huangqi decoction for the treatment of NAFLD.

To provide new ideas for further research and treatment of nonalcoholic fatty liver fibrosis, we used bioinformatics technology to search the gene microarray data related to this disease and identified differentially expressed genes and potential therapeutic drugs. Gene Expression Omnibus (GEO) was used to search the entry of "nonalcoholic fatty liver fibrosis"; the GSE109345 microarray data was downloaded, the differentially expressed genes in the control group and the fibrosis model group were screened with the BioJupie analysis platform, and GO function, KEGG pathway, protein-protein interaction (PPI) network analysis and visualization were conducted for the differentially expressed genes. Finally, through the Connectivity Map (CMap) data platform, compounds with potential efficacy on nonalcoholic fatty liver fibrosis were predicted. A total of 109 differentially expressed genes were screened, including 70 up-regulated genes and 39 down-regulated genes. Functional analysis showed that differentially expressed genes were mainly involved in protein kinase B signal transduction, extracellular domain function, small molecule binding and other functions; pathway analysis showed that these genes participated in retinol metabolism, steroid hormone synthesis, and arachidonic acid metabolism; PPI network analysis showed that metallopeptidase inhibitor 1 (TIMP1), chemokine (C-C motif) ligand 2 (CCL2), recombinant signal regulatory protein beta 1 (SIRPB1), and cytochrome P450 (CYP) were the main genes related to nonalcoholic fatty liver fibrosis. CMap analysis showed that pioglitazone, midodrine, arecoline and other compounds had potential efficacy in nonalcoholic fatty liver fibrosis. Thus, by screening for differentially expressed genes, related genes and potential therapeutic compounds effective in the treatment of non-alcoholic fatty liver fibrosis can be identified, as well as new ideas and approaches for the clinical treatment of non-alcoholic fatty liver fibrosis.

Twenty compounds were isolated and purified from the fresh roots of Huaizhong NO.1 Rehmannia glutinosa by various chromatographic techniques such as Toyopreal HW-40C, Sephadex LH-20, silica gel and semi-preparative HPLC. Their structures were identified by analysis of physicochemical properties and spectral data, and determined as 3-methyl-2-(hydroxymethyl)-4H-pyrone-4-one (1), 3-amino-2-pyridine ethanol (2), (5'S)-2-oxo-N-phenylpyrrolidine-3-carboxamide (3), L-pyroglutamic acid methyl ester (4), indazole (5), uridine (6), adenosine (7), rehmanalkaloid C (8), 1-(3-ethylphenyl)-1, 2-ethanediol (9), (3-ethylphenyl)-1, 2-ethanediol (10), 2-hydroxymethylphenyl-1-O-β-D-glucopyranoside (11), mussaenoside (12), 11-methylforsythide (13), 7-deoxygardoside (14), 1-O-α-L-rhamnopyranosyl(1→6)-β-D-glucopyranoside (15), 6-deoxy-D-mannono-1, 4-lactone (16), monoethylfumarate (17), daphneresinol (18), dihydroquercetin (19), rhamnopyranosyl vaniloyl (20). Compound 1 is a new compound, named as 3-methyl-2-(hydroxymethyl)-4H-pyrone-4-one, compounds 2 and 3 are new natural products, and compounds 4, 5, 9-11, 13, 14 and 16-19 are isolated from Rehmannia for the first time.

In this study, 9 aztreonam prodrug compounds were designed and synthesized, and their metabolic stability in plasmas of different species (rat, mouse, dog, monkey and human) were evaluated. Species differences were observed in aztreonam carboxylates's sensitivity to the plasma esterases among different species, and the hydrolysis rates of aztreonam carboxylates in rodent plasmas were much higher than in non-rodent plasmas. Moreover, the hydrolysis rates of aztreonam carboxylates might be positively correlated with the ClogP values in human plasma. These results provide useful guidance for the further development of monocyclic β lactam prodrugs.

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.

The study was undertaken to clarify the differences in metabolite groups between Aster yunnanensis and Pulicaria insignis to establish plant origin and identify plant resources. Non-target metabolomics of A. yunnanensis and P. insignis was undertaken with sample derivatives and gas chromatography-mass spectrometry (GC-MS). Principal component analysis (PCA), partial least-squares discriminant analysis (PLS-DA) and orthogonal partial least squares-discriminant analysis (OPLS-DA) were used to characterize the differing metabolites of A. yunnanensis and P. insignis. Correlation analysis of these metabolites and metabolic pathway analysis allowed us to identify metabolic pathway changes between samples. Characterization of the antibacterial activity of the essential oil from A. yunnanensis and P. insignis showed that 384 metabolites were identified in the two species, including amino acids and peptides, phenylpropanoids, aromatics, glycoside, nucleotide, flavonoid, alkaloids, saccharides, vitamin, organic acid, lipids, esters, alcohol. A total of 92 differential metabolites with significant differences in content (P < 0.05, VIP > 1) were identified. In conclusion, a new method based on pre-column derivatives and GC-MS metabolomics was used to distinguish and compare A. yunnanensis and P. insignis metabolites.

This article intended to build a component-target network to screen the effective components of Compound Suanzaoren Decoction, and to establish an efficient and rapid method for the determination of effective components. 103 compounds in the Compound Suanzaoren Decoction were identified by HPLC-Q-TOF MS/MS. 27 potential effective substances were analyzed by network pharmacology. The first six components with the largest degree were selected as effective components, including neomangiferin, mangiferin, ferulic acid, senkyunolide Ⅰ, spinosin, and 6'''-feruloylspinosin. A UHPLC method was established for determination. The chromatographic separation was performed on a Waters CORTECS T3 column (2.1 mm×150 mm, 1.6 μm) with the mobile phase of 0.1% phosphoric acid solution and acetonitrile. The results showed that the specificity was good with no interference for the chromatographic peaks. The linear was excellent within the scope of investigation, with the values of r higher than 0.999 0 for all analytes. The method had been verified to have good sensitivity, precision, accuracy, durability and stability. Therefore, the results showed that the method established was suitable for the screening and determination of effective components in Compound Suanzaoren Decoction, which provided a basis for the quality evaluation of traditional Chinese medicine.

A model for quality evaluation was developed by determination of multi-index components in Scutellaria baicalensis Georgi. Eight flavonoids in Scutellaria baicalensis Georgi were quantified by high performance liquid chromatography (HPLC), and a quantitative analysis of multi-components with a single marker (QAMS) method with baicalin as the internal reference substance was established. The 2, 2'-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt (ABTS⁺) method was applied to determine the antioxidant activity of different batches of Scutellaria baicalensis Georgi. Grey relevance analysis was conducted to calculate the grey correlation coefficients of each antioxidant in the herb. The holistic quality of 75 batches of collected samples from different product regions was evaluated to distinguish different commercial types of Scutellaria baicalensis Georgi. The relative correction factor (RCF) of each index component with baicalin as the internal reference indicated good applicability, and there was no significant difference in assay results between the QAMS method and the external standard method (ESM). The results of grey correlation analysis showed that the content of eight index components including baicalin correlated strongly with the antioxidant activity of Scutellaria baicalensis Georgi. The calculated grey relational coefficient ranged from 0.772 4 to 0.808 6. The content of oroxylin A-7-O-β-D-glucuronide, norwogonin-7-O-β-D-glucuronide, baicalein, wogonin and oroxylin A showed positive correlations with the antioxidant potency. In contrast, baicalin, wogonoside and viscidulin Ⅲ content exhibited negative correlations. The ratio of the flavonoid glycosides and flavonoid glycoside aglycones were found to be a critical factor to distinguish the different types of commercial herbs. The crude herbs could be characterized as Scutellaria baicalensis pith-decayed with a G/A ratio less than 10, and the ratio in Scutellaria baicalensis pith-not decayed should be more than 10. The QAMS method established in this study is simple and accurate, and can be used for the determination of eight flavonoids in Scutellaria baicalensis Georgi. Combined with ABTS⁺ antioxidant activity and grey correlation analysis, a comprehensive model for Scutellaria baicalensis Georgi quality determination based on biological activity was established, which provides new ideas and methods for the establishment of quality standards consistent with the characteristics of traditional Chinese medicine.

The three polymorphs (Ⅰ, Ⅱ, Ⅲ) and one amorphous (Ⅳ) form of imatinib-oxalate new salt were prepared and characterized by powder X-ray diffraction, differential scanning calorimetry, thermogravimetric analysis and infrared spectroscopy, and transformation rules among the four salts were analyzed. The solubility of polymorph Ⅱ was investigated by high performance liquid chromatography. The results show that polymorph Ⅱ was stable but polymorph Ⅰ, Ⅲ and amorphous Ⅳ were unstable at room temperature. Polymorph I transformed into polymorph Ⅱ at room temperature. At relative humidity 90%, polymorph Ⅰ, Ⅱ and amorphous Ⅳ transformed into polymorph Ⅲ, but polymorph Ⅲ transformed into amorphous Ⅳ at 70 ℃. The solubility of imatinib was significantly improved after being salted with oxalic acid, and the equilibrium solubility of polymorph Ⅱ in pH 6.8 buffer solution and pure water was increased by 4.1 and 21.2 fold, respectively, as compared to bulk drug. This research provides guidance for the development and quality control of a new salt form of imatinib.

Hesperidin nanosuspensions (HDN-NS) were prepared with tea saponin (TS) as stabilizer. The feasibility of TS as a natural stabilizer and the mechanism of TS stabilized nanosuspensions were investigated to provide reference for the development of green nano-preparations of hesperidin. HDN-NS was prepared by high-speed shearing combined with high-pressure homogenization. Using average particle size and polydispersity index as evaluation indexes, the effects of drug concentration, shearing speed, shearing time, homogeneous pressure and homogeneous cycles on HDN-NS were investigated by single factor experiment. The results of single factor investigation were as follows: drug concentration was 8.0 mg·mL^-1, shearing speed was 16 000 r·min^-1, shearing time was 2 min, the homogeneous cycles were 6 cycles at 35 MPa and 12 cycles at 100 MPa. The pH, ionic strength, zeta potential and critical micelle concentration of TS were investigated to determine the role of electrostatic repulsion in the mechanism of TS stabilized nanosuspensions. The results showed that electrostatic repulsion is involved in the mechanism of TS stabilized HDN-NS. In conclusion, at low concentration, TS can significantly reduce the particle size of HDN-NS, which indicates that TS has the potential to stabilize nanosuspension. Electrostatic repulsion is one of the mechanisms of TS stabilizing nanosuspension.

Clarithromycin (CLA) belongs to the second generation macrolide antibiotic. The commercial crystal form of CLA is form Ⅱ, and it exhibits the poor compressibility during the tablet pressing process. Since the crystal form of drugs has a significant effect on their mechanical properties, from the perspective of crystallography, this study investigated the difference of the compressibility between CLA form Ⅰ and form Ⅱ, and analyzed the mechanism that led to such difference. On the other hand, from the perspective of pharmaceutics, we also studied the effect of filler on the compressibility of form Ⅱ. It was found that CLA form Ⅰ had improved plastic deformation than form Ⅱ because of the slip planes in its crystal structure leading to the better compressibility. Moreover, microcrystalline cellulose, pre-gelatinized starch and lactose monohydrate could improve the compressibility of form Ⅱ, and microcrystalline cellulose showed the best effect. We improve the compressibility of CLA from crystal form and filler, and also lay a foundation for the development of CLA solid preparations.

The MIKC-type MADS-box gene family plays an important role in flower development in plants. This study identifies members of the MIKC-type gene family in Cannabis sativa L. at the genome level, with the chromosomal location and linkage, evolutionary relationships, and identification of conserved motifs determined using bioinformatics tools. The results show that C. sativa contains 39 members of the MIKC-type MADS-box gene family (named CsMADS1-CsMADS39) unevenly distributed on nine chromosomes. The encoded proteins range in length from 146 to 503 amino acids, and the theoretical isoelectric points range from 5.19 to 10.12. Molecular weights range from 16 739.35 to 57 070.56 Da. The subcellular location of CsMADS genes is mainly in the nucleus. The result of conserved domain analysis showed that all genes contain the MADS conserved domain. The analysis of GO showed that all genes were annotated to 331 GO terms, which were clustered by molecular function. A phylogenetic tree showed that CsMADS genes could be divided into 14 subclasses, according to ABCDE homologous gene model; CsMADS genes are clustered with SQUA/AP1, AP3, PI, GGM13, AG, SEP/AGL2 subfamilies in Arabidopsis. There are abundant cis-acting elements in the upstream promoter region of CsMADS genes, mainly light regulatory elements. The results of real-time fluorescent quantitative PCR showed that some CsMADS genes are highly expressed in flowers and bracts, with tissue-specific expression. This study identified and analyzed the MIKC-type MADS-box gene family in C. sativa at the genome level, and provides a theoretical basis for further exploration of the function of MIKC-type genes and their role in regulating the growth and development of medicinally important hemp.

The plant-specific WRKY transcription factor family is involved in the regulation of the response of plants to various environmental factors and biological stress. To study the role of the BcWRKY70 gene in Bupleurum chinense DC., we cloned the open reading frame (ORF) sequence of the BcWRKY70 gene based on the transcriptome database. Bioinformatics analysis of BcWRKY70 and promoter region analysis was carried out, and real-time qRT-PCR was used to detect the expression pattern of BcWRKY70 in different tissues and under the different hormone treatments. The results show that the BcWRKY70 ORF is 948 bp in length, encoding 316 amino acids with a typical WRKY domain. Phylogenetic analysis showed that BcWRKY70 is closely related to GhWRKY70. Its promoter region contains cis-elements that presumably respond to environmental factors such as drought, methyl jasmonic acid (MeJA), and abscisic acid (ABA). qRT-PCR analyses showed that BcWRKY70 is most highly expressed in roots and can quickly respond to MeJA and ABA induction. This study provides a basis for further research on the molecular mechanism of BcWRKY70 in B. chinense DC. resistance.

In recent years, many biosimilars have been approved marketing authorization in our country. When conducting research and evaluation of biosimilar, the quality similarity between the candidate drugs and the original drugs is the key point of "biosimilar", meanwhile it is the basis for clinical and marketing authorization of biosimilar. However, the industry and regulatory agencies are facing many challenges in establishing quality "similarity assessment criteria", such as: limited batches of original drugs; quality drift caused by manufacture process changes in the life cycle; analytical method of critical quality attributes is different from different manfactures; statistical methods used for establishing assessment criteria are difficult to unify. In the article, the data obtained from 69 lots of chemistry, manufacturing and control (CMC) dossier of trastuzumab originator company and dossiers of 9 biosimilar companies were analyzed. Furthermore, combined with the risk identification of the critical quality attributes of the product, quality "similarity assessment criteria" have been proposed. This standard has been verified by the disclosure of biosimilar quality data, aim to promote the development and evaluation of trastuzumab biosimilar.