A novel and low-toxic peptide DR3penA alleviates pulmonary fibrosis by regulating the MAPK/miR-23b-5p/AQP5 signaling axis

Pulmonary fibrosis (PF) is a pathological change caused by repeated injuries and repair dysfunction of the alveolar epithelium. Our previous study revealed that the residues Asn3 and Asn4 of peptide DR8 (DHNNPQIR-NH2) could be modified to improve stability and antifibrotic activity, and the unnatural hydrophobic amino acids α-(4-pentenyl)-Ala and d-Ala were considered in this study. DR3penA (DHα-(4-pentenyl)-ANPQIR-NH2) was verified to have a longer half-life in serum and to significantly inhibit oxidative damage, epithelial-mesenchymal transition (EMT) and fibrogenesis in vitro and in vivo. Moreover, DR3penA has a dosage advantage over pirfenidone through the conversion of drug bioavailability under different routes of administration. A mechanistic study revealed that DR3penA increased the expression of aquaporin 5 (AQP5) by inhibiting the upregulation of miR-23b-5p and the mitogen-activated protein kinase (MAPK) pathway, indicating that DR3penA may alleviate PF by regulating MAPK/miR-23b-5p/AQP5. Safety evaluation showed that DR3penA is a peptide drug without obvious toxicity or acute side effects and has significantly improved safety compared to DR8. Thus, our findings suggest that DR3penA, as a novel and low-toxic peptide, has the potential to be a leading compound for PF therapy, which provides a foundation for the development of peptide drugs for fibrosis-related diseases.

Research progress on the puerarin derivatization through biocatalysis / 药学学报

Puerarin, also known as daidzein 8-C-glucoside, is a major isoflavone glycoside from Pueraria lobata. Puerarin has been shown to possess a variety of pharmacological activities. It has been widely used for the treatment of cardiovascular and cerebrovascular diseases. However, the further applications are limited due to its low water solubility and poor bioavailability. Structural modification is thus regarded as an efficient approach to improve the solubility and bioavailability of puerarin. Unlike chemical modifications, enzyme-assisted modifications, namely biocatalysis, is a promising alternative for the regioselective synthesis of puerarin derivatives due to its high selectivity. Up to date, acylation, glycosylation and hydroxylation of puerarin had been achieved through enzyme-based biocatalysis. Diverse active puerarin derivatives with improved solubility and bioavailability have been thus developed. Based on modification groups, this paper focused on the progress in the preparation of puerarin derivatives by biocatalysis, in which the whole-cells or pure enzymes were used as the biocatalysts. This article was expected to provide new ideas for the synthesis and development of puerarin drugs.

Synthesis and cytotoxic activities of podophyllotoxin derivatives / 中草药

Objective: To modify the structure of podophyllotoxin derivatives and evaluate the antitumor activities of the derivatives. Methods: The target compounds were synthesized by multi-step reaction with podophyllotoxin and aldehyde compound as starting material.. MTT assay was used to test antitumor activity of all the target compounds on Hela cells, K562 cells, and K562/A02 cell. Results: Eleven novel derivatives were synthesized which had not been reported in any literature and the structures were characterized by 1H-NMR, 13C-NMR, HR-ESI-MS and melting point determination analysis. The antitumor activity screening results showed that all the target compounds had different degrees of cytotoxic activity in vitro. Most of the compounds had significant anti-MDR activity in vitro. Conclusion: Through structural modification of podophyllotoxin derivatives, the antineoplastic activities are enhanced.

Synthesis and hepatoprotective activity of Mannich base derivatives of silybin / 药学学报

Two novel Mannich base derivatives of silybin, SLB-DEA and DHSLB-PIP, were designed and synthesized. All the structures of new Mannich base derivatives of silybin were characterized by 1H NMR and HR-MS. Their protective action against CCl4-induced liver injury in mice were investigated. The changes of alanine aminotransferase (ALT), aspartate transaminase (AST), lactate dehydrogenase (LDH), total cholesterol (TC) and triglyceride (TG) were determined and the histopathological changes in liver tissues were examined. Pretreatment with a higher dosage of DHSLB-PIP (40 mg·kg-1) prevented CCl4-induced liver injury as indicated by the reduced levels of ALT, AST, LDH and TG. Meanwhile, liver histopathological improvement was observed in the model groups. The pharmacokinetics study in rats showed that the relative bioavailability of SLB-DEA and DHSLB-PIP were 172.5% and 259.8% compared with silybin. All the results suggest that SLB-DEA and DHSLB-PIP may protect liver against injury by CCl4 and the relative bioavailability was significantly increased, which is worth of further investigation for their druggability.

Bioinformation analysis of chorismate synthase in Baphicacantus cusia and other 78 species of plants / 中国中药杂志

Chorismate synthase(CS, EC:4.2.3.5) catalyses 5-enolpyruvy-shikimate-3-phosphate to form chorismate, which is the essential enzyme for chorismate biosynthesis in organisms. The amino acid sequences of CS from 79 species of higher plants were reported in GenBank at present. 125 amino acid sequences of CS from Baphicacanthus cusia and other 78 species of plants were predicted and analyzed by using various bioinformatics software, including the composition of amino acid sequences, signal peptide, leader peptide, hydrophobic/hydrophilic, transmembrane structure, coiled-coil domain, protein secondary structure, tertiary structure and functional domains. The phylogenetic tree of CS protein family was constructed and divided into eight groups by phylogenetic analysis. The homology comparison indicated that B. cusia shared a high homology with several plants such as Sesamum indicum, Nicotiana tabacum, Solanum tuberosum and so on. The open reading frame(ORF) of all samples is about 1 300 bp, the molecular weight is about 50 kDa, the isoelectric point(pI) is 5.0-8.0 which illustrated that CS protein is slightly basic. The ORF of CS we cloned in B. cusia is 1 326 bp, the amino acid residues are 442, the molecular weight is 47 kDa and pI is 8.11. The CS in B.cusia showed obvious hydrophobicity area and hydrophilicity area, no signal peptide, and may exists transmembrane structure areas. The main secondary structures of CS protein are random coil and Alpha helix, also contain three main structural domains which are an active structural domain, a PLN02754 conserved domain and a FMN binding site. The acquired information in this study would provide certain scientific basis for further study on structure-activity relationship and structure modification of CS in plants in the future.

Discussions on diversity of new drug creation in China / 中草药

It is a long journey to create a new medicine from discovering the lead to market, which deal with various fields and aspects. There are also many ways and entrances or starting points for the creation of a new medicine. In this article, the following aspects including the ways from traditional Chinese materia medica, folk herbal medicine, active components, and structure modification involved in new medicine creation were discussed. Biomimetic syntheses, metabolites, and key technologies to affect the creative medicine were also summarized based on author's experiences. It is expected to be referenced information and inspired for the colleagues.

Research progress of structural modification of oridonin / 药学实践杂志

Oridonin is an en-kaurene diterpenoids compound which was found to have effect on tumor in vitro.But the clinical application has been limited because of poor water solubility,low bioavailability and oral absorption.Many scholars conducted a large number of structure modification researches of oridonin to search for new diterpenes with higher bio-activities and better bio-availabilities,and to develop new antitumor drugs.In this paper,studies on this aspect of oridonin were re-viewed.

Synthesis and bioactivity evaluation of novel chlorogenic acid derivatives containing amide group / 中国药学杂志

OBJECTIVE: To design and synthesize a series of chlorogenic acid derivatives in order to improve the solubility and lipid-water partition coefficients of chlorogenic acid, and test the bioactiviteies of the target compounds. METHODS: The target compounds were synthesized from chlorogenic acid by three-step reactions of hydroxyl protection, acylation, and deprotection. The antitumor activities of the compounds were evaluated against two different tumor cell lines by MTT assay, and the DPPH method was used to measure the antioxidant activities of the compounds. RESULTS: Eight title compounds were prepared, the structures of the compounds were confirmed by IR and NMR. The MTT assay showed that the compounds exhibited certain antitumor activities and better antioxidant activities, and the activities against A-549 and SGC-7901 tumor cells and the scavenging ratio to DPPH· were similar to those of chlorogenic acid. CONCLUSION: Chlorogenic acid derivatives containing amide group still have antitumor and antioxidant activities.

Synthesis and anti-myocardial ischemia activities of novel Danshensu derivatives / 药学实践杂志

Objective To design and synthesize novel Danshensu derivatives in order to improve their stability and cardio-protective effect against myocardial ischemia .Methods Novel Danshensu derivatives were synthesized chiefly viaesterification , methoxy phenol hydroxyl protection ,nitration and amine solution reaction .All the target compounds were evaluated their bio-logical effects on anti-myocardial ischemia with H9c2 cells in vitro .Results 15 compounds were synthesized and further con-firmed by 1 H NMR and MS .Pharmacological studies showed that few synthetic derivatives at 5μmol/L performed a higher bi-ological effect than Danshensu .Conclusion Most derivatives didn't show the best activity at the chosen concentration gradient that a further pharmacological trial need to be done .

Study on Synergistic Hypoglycemic ActivityIn Vitroof Three Kinds of Isoflavone in Chickpea and Its Derivatives of Ethoxylation / 世界科学技术-中医药现代化

Through the ethoxylation structure modification of three isoflavones which were genistein, biochanin A and formononetin in chickpea, the hypoglycemic activity and the synergistic hypoglycemic activity were studied. Ethoxylation structure modification was given on three kinds of isoflavones. The hypoglycemic activity of three kinds of isoflavones and their derivatives were studied. The synergistic hypoglycemic activity of the compounds was also studied. The insulin-resistance HepG2 cell was selected as the model of hypoglycemic activity screening. The results showed that four ethoxylation products were synthesized. And the hypoglycemic activity of genistein was better than biochanin A and formononetin with significant difference (P 0.05). Effects of the compound b and compound c were not as good as the compound a and compound d. There was statistical difference (P 0.05). It was concluded that the combinations of compounds played synergistic effects with better hypoglycemic effect. It provided a basis for developing hypoglycemic agents with the intellectual property rights.

Structure modification of cis-stilbenoids from the tubers of Scirpus yagara and their anti-inflammatory activities / 中国药学杂志

OBJECTIVE: To synthesize cis-stilbenoids derivatives and investigate their anti-inflammatory activities in vitro. METHODS: Sciryagarol I(1) from the tuber of Scirpus yagara, was used as a primary material. The synthetic derivatives were obtained via methyltion, acetylation, and demethylation. MTT assay was used to detect the effects of compound 1, its synthetic derivatives 3-5 and sciryagarol II(2) on RAW264.7 cells viability. And the inhibitory activities of compounds 1-5 against TNF-α and IL-6 production in LPS- and Pam3csk4-activated RAW264.7 cells were evaluated by ELISA assay. RESULTS: The compounds 3-5 were synthesized, and their structures were characterized by 1H-NMR and HRESI-MS spectra. ELISA assay showed that compounds 1, 2 and 5 significantly inhibited the production of TNF-α and IL-6 from LPS- and Pam3csk4-stimulated RAW264.7 cells. CONCLUSION: Three novel compounds 3-5 are synthesized. The number of phenolic hydroxyl in the structure of cis-stilbenoids may be related to their anti-inflammatory activities.

Basic Knowledge and Research Progress on Cantharidin-based Molecules / 世界科学技术-中医药现代化

This study was aimed to summarize main-bone structure of cantharidin-based small molecules and facts about three typical candidates including its origin, physical-chemical properties and general synthetic approaches. Basic chemical and pharmacological information as well as development of anti-cancer activities, which were related to cantharidin, norcantharidin and their analogues were reviewed, especially the relationship between the structures and their inhibitory activity and selectivity of serine-threonine protein phosphatases PP1, PP2A and PP2B in cancer treatment. The designs and developments of new biological cantharidin-based small molecules were also reviewed.

Synthesis of levamisole ferulate and its effects on immune function of mice / 中国药学杂志

OBJECTIVE: To prepare levamisole ferulate (LF) and investigate its effects on the immune function of mice with low immunity, thus to provide basic evidence for regulation of the immune status of animals and improvement of body's defense. METHODS: LF was synthesized by levamisole hydrochloride and sodium ferulate. The model of immune inhibited mice was established by intraperitoneal injection with cyclophosphamide (CTX). In order to verify and compare the effect of immune enhancement, a series of parameters were determined such as the immune organ index, the serum IgA, IgG and IgM in cyclophosphamide-induced-immunosu-pressed mice. RESULTS: The product was obtained and its yield was 80.49%. The identification of the product was done by means of elemental analysis, TLC, UV-Vis, IR and ESI-MS. LF significantly increased the contents of IgM and IgG in cyclophosphamide-in-duced-immunosupressed mice and improved the thymus and spleen indexes. CONCLUSION: This synthetic technique is simple and feasible. LF can significantly regulate the immune function in mice. Copyright 2012 by the Chinese Pharmaceutical Association.

Study on anti-tumor activities of ginsenoside structure modification HRG in vivo / 中国药学杂志

OBJECTIVE: To explore the anti-tumor activities of a new compound 3β,12β,20(S)-trihydroxy dammarane-3-O-β-D-glucopyranosyl (1-2)-β-D-glucopyranoside (HRG), which is a substance of ginsenoside structure modification, in vivo. METHODS: Liver cancer H22 tumor model on the chick chorioallantoic membrane (CAM) was established to observe the effects of HRG on tumor growth, the number of induced vessels and the growth inhibition rate. The implanted tumors were dyed by hematoxylin-eosin (HE), and the morphological properties were studied with light microscope. Immunohistochemistry (SP method) was used to detect the expressions of the implanted tumor's MVD and VEGF. RESULTS: HRG inhibited the tumor growth at 25, 50 and 100 μg · mL-1. Compared with the model control group, the inhibitory rates of the tumor growth were 27.73%, 50.02%, and 64.21%, respectively. HRG significantly reduced the number of tumor-induced vessels. At the same time, there existed different degree necrosis among the treatment groups, and the degree of necrosis had an inverse relationship with the number of tumor-induced vessels. In addition, HRG reduced the MVD of the implanted tumors, and decreased the expression of VEGF. CONCLUSION: HRG has good anti-tumor activities in vivo, and can significantly inhibit the growth of liver cancer H22-CAM tumor and the induction of angiogenesis. The mechanisms may be associated with lower tumor MVD and VEGF expression.