Structure-Based Design of "Head-to-Tail" Macrocyclic PROTACs.

Macrocyclization is a compelling strategy for conventional drug design for improving biological activity, target specificity, and metabolic stability, but it was rarely applied to the design of PROTACs possibly due to the mechanism and structural complexity. Herein, we report the rational design of the first series of "Head-to-Tail" macrocyclic PROTACs. The resulting molecule exhibited pronounced Brd4 protein degradation with low nM DC values while almost totally dismissing the "hook effect", which is a general character and common concern of a PROTAC, in multiple cancer cell lines.

[Analysis of therapeutic mechanism of against colitis-associated colorectal cancer based on network pharmacology and validation in mice].

Objective: To explore the therapeutic mechanism of (LSW) against colitis-associated colorectal cancer (CAC) by network pharmacology.

Methods: TCMSP, BATMAN-TCM, CNKI, PubMed, Genecards, OMIM, and TTD databases were used to obtain the related targets of LSW and CAC. The common targets of LSW and CAC were obtained using Venny online website.

Comparative Analysis of Aristolochic Acids in Medicinal Herbs and Evaluation of Their Toxicities.

Aristolochic acids (AAs) are a group of nitrophenanthrene carboxylic acids present in many medicinal herbs of the genus that may cause irreversible hepatotoxicity, nephrotoxicity, genotoxicity and carcinogenicity. However, the specific profile of AAs and their toxicity in plants, except for AAs Ι and ΙΙ, still remain unclear. In this study, a total of 52 batches of three medicinal herbs belonging to the Aristolochia family were analyzed for their AA composition profiles and AA contents using the UPLC-QTOF-MS/MS approach.

Novel PHD2/HDACs hybrid inhibitors protect against cisplatin-induced acute kidney injury.

Acute kidney injury (AKI) is associated with high morbidity and mortality. Cisplatin is a common chemotherapeutic, but its nephrotoxicity-driven AKI limits its clinical application. Currently, there are no specific and satisfactory therapies in the clinic for AKI.

New cytotoxic ergosterols from a plant-associated fungus .

Three new ergosterols, colletosterols A-C (-), together with two known analogues and , were isolated from the endophytic fungus associated with the leaves of by a bioassay-guided fractionation method. The new structures were elucidated on the basis of extensive spectroscopic analyses and electronic circular dichroism (ECD) calculations. All the ergosterols were evaluated for their cytotoxic activities against A549 and HeLa cell lines.

[Secondary metabolites of Streptomyces sp. A1693].

By means of various chromatographic methods such as Sephadex LH-20，ODS，and semi-preparative HPLC，ten compounds were isolated from Streptomyces sp. A1693 and their structures were elucidated on the basis of spectroscopic data and physico-chemical methods. The compounds comprised 5 butenolides，2 diketopiperazines，and 3 antimycin antibiotics.

NMR-based metabonomics study on the effect of Gancao in the attenuation of toxicity in rats induced by Fuzi.

Ethnopharmacological Relevance: Fuzi, the processed lateral root of Aconitum carmichaelii Debeaux, is a traditional Chinese medicine used for its analgesic, antipyretic, anti-rheumatoid arthritis and anti-inflammation effects; however, it is also well known for its toxicity. Gancao, the root of Glycyrrhiza uralensis Fisch., is often used concurrently with Fuzi to alleviate its toxicity.

[Synthesis and immunosuppressive effects of novel phthalazine ketone derivatives].

A series of phthalazine ketone compounds were synthesized and the structures were confirmed by H NMR and HR-MS spectrum. All target compounds were obtained through 7 steps, including selective reduction, nitration, bromination, ring enlargement, reduction, Knoevenagel and acylated reaction. The compounds were evaluated for their immunosuppressive effects of T-cell proliferation and inhibitory activity of IMPDH type II in vitro, as well as their structure-activity relationship were assessed.

Protective effects of radix Rosa laevigata against Propionibacterium acnes and lipopolysaccharide-induced liver injury.

We investigated the effects of an extract of Radix Rosa laevigata (R. R. laevigata) on Propionibacterium acnes (P.

The anti-stress effects of Sarcandra glabra extract on restraint-evoked immunocompromise.

Sarcandra glabra was a renowned herb traditionally used as herbal tea or food supplement to enhance mental efficiency and to recover from stress or fatigue in China. We investigated the effects of Sarcandra glabra extract (SGE), with chemical composition clearly showed by HPLC fingerprint as quality control, on immunologic response including natural killer (NK) cell activity and its antioxidative capacity in splenocytes obtained from restraint mice. Our results found that daily oral administration of SGE (125, 500 mg/kg/d) for 5 consecutive days to restrained mice alleviated the stress-induced reduction of the number of lymphocytes, the balance of CD4(+) T/CD8(+) T and NK cell activity per spleen.

Construction, detection and microarray analysis on Shigella dysenteriae a1 IroN, ShuA single, double mutants.

In this study, we constructed single mutants MTS-1, MTS-2 of IroN and ShuA gene and double mutant MTS of them in Shigella dysenteriae A1 strain 51197 by insert and absence. The functional detection of every mutant was performed at the level of culture medium and cell experiment. The gene expression profiles of the mutants and the wild-type strains under iron-enriched and iron-limited conditions were analyzed by the SD51197 whole genomic microarray.

[Phenolic acid derivatives from the rhizome of Fagopyrum cymosum].

Objective: To study the chemical constituents of Fagopyrum cymosum.

Method: The chemical constituents were isolated by various chromatographic methods and their structures were elucidated by the analysis of spectral data and physiochemical properties.

Result: Four phenolic acid derivatives were isolated from F.

[Effects of ginsenosides on the actions of morphine].

The effects of ginsenosides on the actions of morphine are summarized. It mainly focuses on the antagonistic effects of ginsenosides on morphine-induced changes of animal behaviors, neural system functions and cell signaling transduction.

[Studies on constituents of the leaves of Lindera aggregata (Sims) Kosterm].

Objective: To study the antibacterial and anti-inflammatory constituents of the leaves of Lindera aggrega.

Method: Compounds were isolated by colum chromatography, and the structures were identified by spectroscopic methods.

Result: Six compounds were isolated and identified as mixture of 6-Acetyllindenanolide B-1 and B-2(I), dehydrolindestrenolide (II), hydroxylinderstrenolide (III), linderalactone (IV), kameofero (V), beta-sitosterol (VI).

Antitumor-promoting constituents from Dioscorea bulbifera L. in JB6 mouse epidermal cells.

An antitumor-promoting effect was found in the extracts/ingredients of a plant used as a traditional medicine in mainland China, using the neoplastic transformation assay of mouse epidermal JB6 cell lines. The ethyl acetate soluble fraction of 75% ethanol extract of the rhizomes of Dioscorea bulbifera L. showed an inhibitory effect against the tumor promotion of JB6 (Cl 22 and Cl 41) cells induced by a promoter, 12-O-tetradecanoylphorbol-13-acetate (TPA).

Metabolism of roxithromycin in phenobarbital-treated rat liver microsomes.

Aim: To investigate the metabolism of roxithromycin (RXM) in rat liver microsomes and the possible effects of RXM and its metabolites on cytochrome P-450 (CYP450).

Methods: Liver microsomes of Wistar rats, induced by phenobarbital, were prepared using ultracentrifuge method. RXM in vitro metabolism was stu died with the microsome incubation.

Furostanol glycosides from bulbs of Allium chinense.

Two new furostanol saponins, named chinenosides II and III, were isolated along with seven known compounds, from the bulbs of Allium chinese G. Don by a combination of silica gel, Diaion HP-20, and octadecylsilanized (ODS) silica gel column chromatographies and preparative HPLC. On the basis of chemical and spectroscopic evidence, the structures of chinenosides II and III were determined to be 26-O-beta-glucopyranosyl 3 beta,26-dihydroxy-(25R)-5 alpha-furost-20(22)-en-6-one 3-O-beta-xylopyranosyl-(1 --> 4)-[alpha-arbinopyranosyl(1 --> 6) ]-beta-glucopyranoside and 26-O-beta-glucopyranosyl 3 beta,26-dihydroxy-(25R)-5 alpha-furost-20 (22)-en-6-one 3-O-alpha-arabinopyranosyl (1 --> 6)-beta-glucopyranoside, respectively.