Biology subjects

Xiang, Y.

Publications and source records attributed to Xiang, Y..

131 records · Page 8Linked to original sources

bioRxiv2018

A naturally-occurring dominant-negative competitor of Keap1 against its inhibition of Nrf2

Transcription factor Nrf2 is a master regulator of antioxidant and/or electrophile response elements (AREs/EpREs)driven genes involved in homeostasis, detoxification and adaptation to various stresses. The cytoprotective activity of Nrf2, though being oppositely involved in both cancer prevention and progression, is critically controlled by Keap1 (Kelch-like ECH-associated protein 1) as an adaptor subunit of Cullin 3-based E3 ubiquitin ligase, that is a key sensor for oxidative and electrophilic stresses. Now, we first report a novel naturally-occurring mutant of Keap1, designated Keap1{Delta}C, which lacks most of its C-terminal Nrf2-interacting domain essential for inhibition of the CNC-bZIP factor. This mutant Keap1{Delta}C is yielded by translation from an alternatively mRNA-spliced variant lacking the fourth and fifth exons, but their coding sequences are retained in the wild-type Keap1 locus (with no genomic deletions). Although this variant was found primarily in the human highly-metastatic hepatoma (MHCC97H) cells, it was widely expressed at very lower levels in all other cell lines examined. No matter whether Keap1{Delta}C retains less or no ability to inhibit Nrf2, it functions as a dominant-negative competitor of Keap1 against its inhibition of Nrf2-target genes. This is due to its antagonist effect on Keap1-mediated turnover of Nrf2 protein.

molecular biology↗

bioRxiv2018

Nach is a novel ancestral subfamily of the CNC-bZIP transcription factors selected during evolution from the marine bacteria to human

All living organisms have undergone the evolutionary selection under the changing natural environments to survive as diverse life forms. All life processes including normal homeostatic development and growth into organismic bodies with distinct cellular identifications, as well as their adaptive responses to various intracellular and environmental stresses, are tightly controlled by signaling of transcriptional networks towards regulation of cognate genes by many different transcription factors. Amongst them, one of the most conserved is the basic-region leucine zipper (bZIP) family. They play vital roles essential for cell proliferation, differentiation and maintenance in complex multicellular organisms. Notably, an unresolved divergence on the evolution of bZIP proteins is addressed here. By a combination of bioinformatics with genomics and molecular biology, we have demonstrated that two of the most ancestral family members classified into BATF and Jun subgroups are originated from viruses, albeit expansion and diversification of the bZIP superfamily occur in different vertebrates. Interestingly, a specific ancestral subfamily of bZIP proteins is identified and also designated Nach (Nrf and CNC homology) on account of their highly conservativity with NF-E2 p45 subunit-related factors Nrf1/2. Further experimental evidence reveals that Nach1/2 from the marine bacteria exerts distinctive functions from Nrf1/2 in the transcriptional ability to regulate antioxidant response element (ARE)-driven cytoprotective genes. Collectively, an insight into Nach/CNC-bZIP proteins provides a better understanding of distinct biological functions between these factors selected during evolution from the marine bacteria to human.\n\nSignificanceWe identified the novel ancestral subfamily (i.e. Nach) of CNC-bZIP transcription factors with highly conservativity from marine bacteria to human. Combination of bioinformatics with genomics and molecular biology demonstrated that two of the most ancestral family members classified into BATF and Jun subgroups are originated from viruses. The Jun and CNC subfamilies also share a common origin of these bZIP proteins. Further experimental evidence reveals that Nach1/2 from the marine bacteria exerts nuance functions from human Nrf1/2 in the transcriptional ability to regulate antioxidant response element (ARE)-driven genes, responsible for the host cytoprotection against inflammation and cancer. Overall, this study is of multidisciplinary interests to provide a better understanding of distinct biological functions between Nach/CNC-bZIPs selected during evolution.

ecology↗

bioRxiv2018

A nuclear hormone receptor and lipid metabolism axis are required for the maintenance and regeneration of reproductive organs

Understanding how stem cells and their progeny maintain and regenerate reproductive organs is of fundamental importance. The freshwater planarian Schmidtea mediterranea provides an attractive system to study these processes because its hermaphroditic reproductive system (RS) arises post-embryonically and when lost can be fully and functionally regenerated from the proliferation and regulation of experimentally accessible stem and progenitor cells. By controlling the function of a nuclear hormone receptor gene (nhr-1), we established conditions in which to study the formation, maintenance and regeneration of both germline and somatic tissues of the planarian RS. We found that nhr-1(RNAi) not only resulted in the gradual degeneration and complete loss of the adult hermaphroditic RS, but also in the significant downregulation of a large cohort of genes associated with lipid metabolism. One of these, Smed-acs-1, a homologue of Acyl-CoA synthetase, was indispensable for the development, maintenance and regeneration of the RS, but not for the homeostasis or regeneration of other somatic tissues. Remarkably, supplementing nhr-1(RNAi) animals with either bacterial Acyl-CoA synthetase or the lipid metabolite Acetyl-CoA rescued the phenotype restoring the maintenance and function of the hermaphroditic RS. Our findings uncovered a likely evolutionarily conserved role for nuclear hormone receptors and lipid metabolism in the regulation of stem and progenitor cells required for the long-term maintenance and regeneration of animal reproductive organs, tissues and cells.

developmental biology↗

bioRxiv2018

Microtubule acetylation is required for mechanosensation in Drosophila

At the cellular level, -tubulin acetylation alters the structure of microtubules to render them mechanically resistant to compressive forces. How this biochemical property of microtubule acetylation relates to mechanosensation remains unknown, though prior studies have shown that microtubule acetylation plays a role in touch perception. Here, we identify the major Drosophila -tubulin acetylase (dTAT) and show that it plays key roles in several forms of mechanosensation while exerting little effect on other sensory modalities. dTAT is highly expressed in neurons of the larval peripheral nervous system (PNS), but is not required for normal neuronal morphogenesis. We show that mutation of the acetylase gene or the K40 acetylation site in -tubulin impairs mechanical sensitivity in sensory neurons and behavioral responses to gentle touch, harsh touch, gravity, and sound stimulus, but not thermal stimulus. Finally, we show that dTAT is required for mechanically-induced activation of NOMPC, a microtubule-associated transient receptor potential channel, and functions to maintain integrity of the microtubule cytoskeleton in response to mechanical stimulation.

cell biology↗

bioRxiv2017

Acute and chronic toxicity assessment of benzylpenicillin G residue in cooked meat

The current level of penicillin use and its persisting residues in livestock is potentially concerning; the toxicity of penicillin residues in heat-treated animal food products (HAFP) is yet to be elucidated. In this study, the acute and chronic toxicity of benzylpenicillin G (BPG) residues in HAFP was investigated in a mouse model. The calculated LD50 of BPG heated to cooking temperature (BPHCT) was 933.04 mg kg-1 [b.w.] intraperitoneally corresponding to 3.75 times lower than its prototype. Mice fed on the experimental diet containing heat-treated beef with high BPG levels for 6 months displayed a reduction in body weight and altered serum values indicating for liver and renal function. Further, the organ ratios of intestinal and spleen were increased. Histopathological changes were observed in the liver, lung and parenchyma testis tissue. BPHCT residue induced sperm aberration and micronucleated polychromatic erythrocytes formation. Present results indicate that prolonged exposure of BPHCT at higher levels of residue might have an impact on public health. Importantly the toxic concentrations of BPHCT are relatively high compared with levels that would result from the degradation of antibiotic residues in meat from animals that have received a therapeutic dose of BPG.

pharmacology and toxicology↗