Ubiquitin-dependent Argonauteprotein MEL1 degradation is essential for rice sporogenesis and phasiRNA target regulation.

MEIOSIS ARRESTED AT LEPTOTENE1 (MEL1), a rice (Oryza sativa) Argonaute (AGO) protein, has been reported to function specifically at premeiotic and meiotic stages of germ cell development and is associated with a novel class of germ cell-specific small noncoding RNAs called phased small RNAs (phasiRNAs). MEL1 accumulation is temporally and spatially regulated and is eliminated after meiosis. However, the metabolism and turnover (i.e. the homeostasis) of MEL1 during germ cell development remains unknown. Here, we show that MEL1 is ubiquitinated and subsequently degraded via the proteasome pathway in vivo during late sporogenesis. Abnormal accumulation of MEL1 after meiosis leads to a semi-sterile phenotype. We identified a monocot-specific E3 ligase, XBOS36, a CULLIN RING-box protein, that is responsible for the degradation of MEL1. Ubiquitination at four K residues at the N terminus of MEL1 by XBOS36 induces its degradation. Importantly, inhibition of MEL1 degradation either by XBOS36 knockdown or by MEL1 overexpression prevents the formation of pollen at the microspore stage. Further mechanistic analysis showed that disrupting MEL1 homeostasis in germ cells leads to off-target cleavage of phasiRNA target genes. Our findings thus provide insight into the communication between a monocot-specific E3 ligase and an AGO protein during plant reproductive development.

Linker Optimization and Therapeutic Evaluation of Phosphatidylserine-Targeting Zinc Dipicolylamine-based Drug Conjugates.

We report that compound 13, a novel phosphatidylserine-targeting zinc(II) dipicolylamine drug conjugate, readily triggers a positive feedback therapeutic loop through the in situ generation of phosphatidylserine in the tumor microenvironment. Linker modifications, pharmacokinetics profiling, in vivo antitumor studies, and micro-Western array of treated-tumor tissues were employed to show that this class of conjugates induced regeneration of apoptotic signals, which facilitated subsequent recruitment of the circulating conjugates through the zinc(II) dipicolylamine-phosphatidylserine association and resulted in compounding antitumor efficacy. Compared to the marketed compound 17, compound 13 not only induced regressions in colorectal and pancreatic tumor models, it also exhibited at least 5-fold enhancement in antitumor efficacy with only 40% of the drug employed during treatment, culminating in a >12.5-fold increase in therapeutic potential. Our study discloses a chemically distinct apoptosis-targeting theranostic, with built-in complementary functional moieties between the targeting module and the drug mechanism to expand the arsenal of antitumor therapy.

Acetylcholinesterase inhibition effects of marine fungi.

CONTEXT: To this day, there are no reports that marine compounds isolated from microorganisms of the Lianyungang area of China have been used for the treatment of Alzheimer's disease. OBJECTIVE: The present study was to isolate fungi from the sea sediment of the Lianyungang area and screen for acetylcholineseterase inhibition activities of ethyl acetate extracts. MATERIALS AND METHODS: Fungi were isolated from the sea sediment and fermented. After centrifugation, the supernate was extracted with ethyl acetate. The ethyl acetate extract was then fractionated into five fractions. Acetylcholinesterase inhibition activities of the ethyl acetate extracts and five sub-fractions were tested at a concentration of 500 µg/mL with the Ellman's method. RESULTS: Forty-three marine fungi were isolated; 15 extracts inhibited acetylcholinestrease >50% and 3 extracts inhibited the acetylcholinesterase >80% at the concentration of 500 µg/mL. The 3 extracts (L1705, S1101, SH0701) inhibited AChE dose-dependently with IC50 values of 11.3 ± 1.2, 72.1 ± 2.3, and 7.8 ± 2.8 µg/mL, respectively. After the extract of SH0701 was fractionated into five fractions, the ethyl acetate fraction possessed the highest acetylcholinesterase inhibitory activity with an inhibition rate of 71.55% at the concentration of 10 µg/mL. The fungus SH0701 was identified as Aspergillus ochraceus SH0701 according to morphology and molecular identification. DISCUSSION AND CONCLUSION: The present results indicates that some ethyl acetate extracts of marine fungi isolated from Lianyungang area of China could inhibit AChE potently. Therefore, some novel AChE inhibitors might exist in those extracts.

Inhibition of urease by extracts derived from 15 Chinese medicinal herbs.

CONTEXT: Helicobacter pylori is a major causative factor in gastritis-like disorders, and urease plays a key role in Helicobacter pylori colonizing and persisting in the mucous layer of the human stomach. In China, a variety of Chinese medicinal herbs have been prescribed to attenuate or eradicate gastritis-like disorders. However, little is known about the urease inhibition of Chinese medicinal herbs. OBJECTIVE: The present study was conducted to investigate the urease inhibition activities of the ethanol and water extracts of 15 Chinese medicinal herbs. MATERIALS AND METHODS: The ethanol and water extracts derived from 15 medicinal herbs, traditionally used for the treatment of gastritis-like disorders in China, were tested for urease-inhibition activity using the phenol red method. RESULTS: Screened at 10 µg/mL, 14 ethanol extracts and 10 water extracts showed urease inhibition. The ethanol extracts of Magnolia officinalis Rehd. et Wils. (Magnoliaceae) and Cassia obtusifolia L. (Leguminosae) possessed inhibition rates higher than 50% with IC50 values of 6.5 and 12.3 µg/mL, respectively. After fractionating successively, the petroleum ether fraction of the ethanol extracts of Magnolia officinalis showed the best activity with 90.8% urease inhibition at a concentration of 10 µg/mL. The bioautography of the petroleum ether fraction indicated the existence of the urease inhibitors in the herb. DISCUSSION AND CONCLUSION: The present results indicated that some Chinese medicinal herbs might treat gastritis-like disorders via the inhibition of Helicobacter pylori urease and the further possibility for discovering useful novel urease inhibitors from the Chinese medicinal herbs.

[Investigation of editions of Wenrebing Zhinan Ji (Collection of Guide for Warm Heat Disease)].

Wenrebing Zhinan Ji (Collection of Guide for Warm Heat Disease) was not a lengthy work, but it had quite a few influences among the medical works of warm heat disease. Regarding the evolvement of the edition and contents of the book, relative records in some authoritative bibliographic tool references had mistakes, errors and defects. The records of the author were complicated and confusing. There were five versions of the book recorded in the Quanguo Zhongyi Tushu Lianhe Mulu (Nationwide Union Catalog of Books of Traditional Chinese Medicine). The study found that there are other versions to be added here, including Wenre Zuiyan (Verbosity of Warm Heat Disease) supplemented to Sanjia Yian Heke (United Collection of Medical Cases of Three Physicians) and Wenre Jingwei (Longitude and Latitude of Warm Heat Diseases) by Wang Mengying, with the xylographic version of Guangxu of the Qing Dynasty excluded. Each version possesses its own special features and values.