Biology subjects

Wang, X.-P.

Publications and source records attributed to Wang, X.-P..

6 recordsLinked to original sources

bioRxiv2024

Peptide Information Compression Technology (PICT): A New Frontier in Therapeutic Peptide Discovery

Therapeutic peptides hold tremendous market potential, yet the discovery methods for active peptides lag considerably behind those for small molecules and biological macromolecule drugs. Due to their respective limitations, traditional peptide compound synthesis and display libraries fail to meet the growing demands of the peptide drug market. Here, we introduce a novel Peptide Information Compression Technology (PICT) and, based on this technology, a large-scale physical peptide library and its accompanying high-throughput screening (HTS) platform. By screening for inhibitors of TSLP/TSLPR/IL7R and antagonists of MC3R at both the molecular and cellular levels, we have identified active molecules in the single-digital micromolar and nanomolar ranges, respectively. This demonstrates the immense application value of Peptide Information Compression Technology in the efficient discovery of peptide drugs.

molecular biology↗

bioRxiv2024

Sortilin C-terminal fragment deposition depicts tangle-related nonamyloid neuritic plaque growth in Alzheimers disease

Sortilin C-terminal fragments (sorfra) can co-deposit in {beta}-amyloid (A{beta}) plaques in human brain. However, sorfra plaques develop in the cerebrum with a spatiotemporal trajectory as of tauopathy. Here we examined sorfra pathogenesis relative to neuritic plaque evolution in the human brains with amyloid and tau pathologies converged in the neocortex and hippocampus. Sorfra plaques occurred in correlation with pTau/tangle, but not A{beta}, pathologies across cerebral regions, neighboring cortical/hippocampal areas, and along the sulcal valley to gyral hilltop transition. Sorfra plaques and neuritic plaques were matchable in location, shape and size between consecutive sections, and were colocalized in double-labeling preparations. Microscopical study and tissue clearance three-dimensional imaging revealed sorfra/A{beta} colocalized as well as independent plaques. Among the former, sorfra labeling correlated negatively to A{beta}/amyloid labeling and {beta}-secretase-1 labeling in dystrophic neurites. Sorfra plaques were depleted of microtubule-associated protein 2 (MAP2) labeled neuronal somata and dendrites, whereas normal looking MAP2/sortilin co-labeled profiles occurred nearby. Sorfra deposits were seen in astrocytes but not microglia around the plaques. Taken together, sorfra plaques are anatomically matchable to silver stained neuritic plaques. They develop with tangle-related somatodendritic degeneration, presenting as nonamyloid growth of the A{beta} plaques and formation of A{beta}-independent neuritic plaques during Alzheimers disease pathogenesis.

neuroscience↗

bioRxiv2024

Receptor tyrosine kinases CAD96CA and FGFR1 function as the cell membrane receptors of insect juvenile hormone

Juvenile hormone (JH) is important to maintain insect larval status; however, its cell membrane receptor has not been identified. Using the lepidopteran insect Helicoverpa armigera (cotton bollworm), a serious agricultural pest, as a model, we determined that receptor tyrosine kinases (RTKs) cadherin 96ca (CAD96CA) and fibroblast growth factor receptor homologue (FGFR1) function as JH cell membrane receptors by their roles in JH-regulated gene expression, larval status maintaining, rapid intracellular calcium increase, phosphorylation of JH intracellular receptor MET1 and cofactor Taiman, and high affinity to JH III. Gene knockout of Cad96ca and Fgfr1 by CRISPR/Cas9 in embryo and knockdown in various insect cells, and overexpression of CAD96CA and FGFR1 in mammalian HEK-293T cells all supported CAD96CA and FGFR1 transmitting JH signal as JH cell membrane receptors.

developmental biology↗

bioRxiv2024

Varying selection pressure for a Na+ sensing site in epithelial Na+ channel subunits reflect divergent roles in Na+ homeostasis

The epithelial Na+ channel (ENaC) emerged early in vertebrates and has played a role in Na+ and fluid homeostasis throughout vertebrate evolution. We previously showed that proteolytic activation of the channel evolved at the water to land transition of vertebrates. Sensitivity to extracellular Na+, known as Na+ self-inhibition, reduces ENaC function when Na+ concentrations are high and is a distinctive feature of the channel. A fourth ENaC subunit, {delta}, emerged in jawed fishes from an subunit gene duplication. Here, we analyzed 846 and {delta} subunit sequences and found that a key Asp in a postulated Na+ binding site was nearly always present in the subunit, but frequently lost in the {delta} subunit (e.g., human). Analysis of site evolution and codon substitution rates provide evidence that the ancestral subunit had the site and that purifying selection for the site relaxed in the {delta} subunit after its divergence from the subunit, coinciding with a loss of {delta} subunit expression in renal tissues. We also provide evidence that the proposed Na+ binding site in the subunit is a bona fide site by conferring novel function to channels comprising human {delta} subunits. Together, our findings provide evidence that ENaC Na+ self-inhibition improves fitness through its role in Na+ homeostasis in vertebrates.

evolutionary biology↗

bioRxiv2023

Mineralocorticoid receptor-independent activation of ENaC in bile duct ligated mice

Sodium and fluid retention in liver disease is classically thought to result from reduced effective circulating volume and stimulation of the renin-angiotensin-aldosterone system (RAAS). Aldosterone dives Na+ retention by activating the mineralocorticoid receptor and promoting the maturation and apical surface expression of the epithelial Na+ channel (ENaC), found in the aldosterone-sensitive distal nephron. However, evidence of fluid retention without RAAS activation suggests the involvement of additional mechanisms. Liver disease can greatly increase plasma and urinary bile acid concentrations and have been shown to activate ENaC in vitro. We hypothesize that elevated bile acids in liver disease activate ENaC and drive fluid retention independent of RAAS. We therefore increased circulating bile acids in mice through bile duct ligation (BDL) and measured effects on urine and body composition, while using spironolactone to antagonize the mineralocorticoid receptor. We found BDL lowered blood [K+] and hematocrit, and increased benzamil-sensitive natriuresis compared to sham, consistent with ENaC activation. BDL mice also gained significantly more body water. Blocking ENaC reversed fluid gains in BDL mice but had no effect in shams. In isolated collecting ducts from rabbits, taurocholic acid stimulated net Na+ absorption but had no effect on K+ secretion or flow-dependent ion fluxes. Our results provide experimental evidence for a novel aldosterone-independent mechanism for sodium and fluid retention in liver disease which may provide additional therapeutic options for liver disease patients. SignificanceAdvanced liver disease is often complicated by renal sodium retention, leading to fluid retention, poor outcomes, and increased mortality. This is currently thought to be driven by increased levels of the hormone aldosterone, although numerous published reports demonstrate normal aldosterone levels in many liver patients with volume overload. Management of these patients relies on diuretics and Na+ restriction, or more invasive procedures with increased risks for diuretic-resistant patients. Here, we report a novel mechanism for fluid retention in liver disease, which provides a basis to develop new strategies to treat fluid retention in these patients.

physiology↗

bioRxiv2020

Activation by Cleavage of the Epithelial Na+ Channel α and γ Subunits Independently Coevolved with the Vertebrate Terrestrial Migration

Vertebrates evolved mechanisms for sodium conservation and gas exchange in conjunction with migration from aquatic to terrestrial habitats. Epithelial Na+ channel (ENaC) function is critical to systems responsible for extracellular fluid homeostasis and gas exchange. ENaC is activated by cleavage at multiple specific extracellular polybasic sites, releasing inhibitory tracts from the channels and {gamma} subunits. We found that proximal and distal polybasic tracts in ENaC subunits coevolved, consistent with the dual cleavage requirement for activation observed in mammals. Polybasic tract pairs evolved with the terrestrial migration and the appearance of lungs, coincident with the ENaC activator aldosterone, and appeared independently in the and {gamma} subunits. In summary, sites within ENaC for protease activation developed in vertebrates when renal Na+ conservation and alveolar gas exchange was required for terrestrial survival.

evolutionary biology↗