Mechanistic convergence and shared therapeutic targets in Niemann-Pick disease.

Niemann-Pick disease type C (NPC) and Tangier disease are genetically and clinically distinct rare inborn errors of metabolism. NPC is caused by defects in either NPC1 or NPC2; whereas Tangier disease is caused by a defect in ABCA1. Tangier disease is currently without therapy, whereas NPC can be treated with miglustat, a small molecule inhibitor of glycosphingolipid biosynthesis that slows the neurological course of the disease. When a Tangier disease patient was misdiagnosed with NPC and treated with miglustat, her symptoms improved. This prompted us to consider whether there is mechanistic convergence between these two apparently unrelated rare inherited metabolic diseases. In this study, we found that when ABCA1 is defective (Tangier disease) there is secondary inhibition of the NPC disease pathway, linking these two diseases at the level of cellular pathophysiology. In addition, this study further supports the hypothesis that miglustat, as well as other substrate reduction therapies, may be potential therapeutic agents for treating Tangier disease as fibroblasts from multiple Tangier patients were corrected by miglustat treatment.

Investigation of the genes associated with a male sterility mutant (msm) in Chinese cabbage (Brassica campestris ssp. pekinensis) using RNA-Seq.

In Chinese cabbage, hybrid seed production is performed using male sterility lines, an important approach to heterosis utilization. In this study, a stably inherited male sterile mutant msm was obtained from the 'FT'-doubled haploid line of Chinese cabbage using isolated microspore culture combined with 60Co γ-ray mutagenesis. The genetic backgrounds of 'FT' and msm were highly consistent; however, compared with wild-type 'FT', msm exhibited completely degenerated stamens and no pollen phenotype. Other characters showed no significant differences. Cytological observations revealed that stamen abortion in msm begins during the tetrad period and that tapetum cells were abnormally expanded and highly vacuolated, leading to microspore abortion. Genetic analysis indicated that the msm mutant phenotype is controlled by a single recessive nuclear gene. Comparative transcriptome analysis of 'FT' and msm flower buds using RNA-Seq technology revealed 1653 differentially expressed genes, among which, a large number associated with male sterility were detected, including 64 pollen development- and pollen tube growth-related genes, 94 pollen wall development-related genes, 11 phytohormone-related genes, and 16 transcription factor-related genes. An overwhelming majority of these genes were down-regulated in msm compared with 'FT'. Furthermore, KEGG pathway analysis indicated that a variety of carbohydrate metabolic and lipid metabolic pathways were significantly enriched, which may be related to pollen abortion. The expression patterns of 24 male sterility-related genes were analyzed using qRT-PCR. In addition, 24,476 single-nucleotide polymorphisms and 413,073 insertion-deletion events were specifically detected in msm. These results will facilitate elucidation of the regulatory mechanisms underlying male sterility in Chinese cabbage.

Pectin methylesterase inhibitor (PMEI) family can be related to male sterility in Chinese cabbage (Brassica rapa ssp. pekinensis).

Pectin-related genes play significant roles in pollen development and pollen tube growth, and their allelic variations are one of the major reasons for the abnormal development of male gametophyte. Currently, little is known about the role of the PMEI family in male sterility of plants. In this study, 97 putative PMEI genes were identified in Brassica rapa genome. By a phylogenetic analysis, the PMEI family was divided into 10 clades with highly conserved structural characteristics. The publically available RNA-seq data on different tissues of B. rapa accession Chiifu-401-42 revealed that 23 PMEI isoforms were flower-specific genes. We created a recessive genic male sterile mutant (ftms) in Chinese cabbage. This mutant was a doubled haploid line with stable inheritance, derived from Chinese cabbage 'FT' generated through a combination of radiation mutagenesis and isolated microspore culture. The transcriptome profiles of the floral buds of ftms and its wild-type line 'FT' were determined using RNA-seq. A total of 17 PMEI genes were found to be differentially expressed; all of them were down-regulated in ftms compared to their levels in 'FT'. Consistent with the transcriptome data, all these genes were observed to be highly expressed in the floral buds of 'FT' using qRT-PCR analysis. Of these, eight genes were specifically expressed in the floral buds of 'FT'; three of these (Bra019903, Bra014099, and Bra032239) were stamen-specific genes. The results contribute to further elucidation of the regulatory mechanisms underlying male sterility in Chinese cabbage.

New flavonoid from Patrinia villosa.

CONTEXT: Patrinia villosa (Thunb.) Juss (Valerianaceae) is an important ancient herbal medicine widely used for inflammation, wound healing, and abdominal pain. But little is known of the phytochemical constituents of this herbal plant. OBJECTIVE: The objective of this study is to isolate and identify the bioactive components from P. villosa. MATERIALS AND METHODS: A 70% EtOH extract of P. villosa was subjected to normal-phase silica, ODS silica gel column chromatography, and semi-preparative HPLC chromatography after partitioned successively with light petroleum, dichloromethane and n-BuOH. Chemical structures of the compounds were elucidated by spectroscopic methods including UV, 1D-NMR, 2D-NMR, HR-ESI-MS, and CD spectra. The cytotoxic activity of the new component was determined with the SMMC-7721 cell line using the MTT method after incubation for 48 h. RESULTS: A new flavonoid named patriniaflavanone A (1) along with four known compounds was isolated from P. villosa. The four known compounds were identified as luteolin 7-O-glucuronide-6″-methyl ester (2), p-hydroxyphenylacetic acid methyl ester (3), trans-caffeic acid (4), and trans-caffeic acid methylate (5) by comparison of their spectral data with the reported data. The IC50 value of patriniaflavanone A (1) on SMMC-7721 was 61.27 µM. DISCUSSION AND CONCLUSION: This is the first report on the isolation and identification of patriniaflavanone A (1), and compounds 2-5 were isolated for the first time from the title plant. Patriniaflavanone A (1) exhibited moderate cytotoxic activity.