Biomedical subjects

Wen Hu

Publications and source records attributed to Wen Hu.

9 recordsLinked to original sources

PubMed2026

Structural basis for small-molecule agonism at GCGR and GIPR via a conserved intracellular allosteric site.

The glucagon receptor (GCGR) and gastric inhibitory polypeptide receptor (GIPR) are class B GPCRs that regulate glucose homeostasis and energy balance, making them key targets for type 2 diabetes and obesity. Achieving preferential Gs signaling at these receptors with small molecules remains an unmet challenge. Here, we report SIM1, developed through optimization of the PCO371 scaffold, which exhibits preferential Gs signaling at GCGR and GIPR with minimal detectable β-arrestin recruitment and substantially improved efficacy at GIPR. Cryo-EM structures of SIM1-GCGR-Gs (2.53 Å) and SIM1-GIPR-Gs (2.74 Å) reveal a shared intracellular allosteric interface at the receptor-G protein coupling region, distinct from extracellular peptide recognition. Structural comparison with GLP1R suggests that intracellular conformational constraints contribute to differential SIM1 responsiveness, which is restored by targeted mutations. Guided by these insights, analogs SIM2 and SIM3 exhibited up to 20-fold enhanced potency while maintaining an apparent preferential Gs signaling profile. These findings reveal a conserved intracellular allosteric activation mechanism across multiple class B GPCRs and identify SIM1 and its analogs as valuable chemical tools for investigating receptor-specific intracellular allosteric regulation and G protein-preferential signaling.

GCGR↗

PubMed2026

Structural basis of β-arrestin coupling and transducer selectivity in PAC1R.

The pituitary adenylate cyclase-activating polypeptide receptor (PAC1R) is a class B G protein-coupled receptor (GPCR) that engages both G proteins and β-arrestins to mediate diverse signaling responses, yet how PAC1R adopts distinct intracellular conformations to achieve this transducer selectivity remains poorly understood. Here, we report the cryo-electron microscopy structure of PAC1R in complex with β-arrestin 1 (βarr1), revealing a core-engaged conformation. Comparison with the Gs-bound PAC1R structure shows that βarr1 engagement is associated with remodeling of the intracellular transmembrane bundle, including TM5 reorientation and inward movement of TM6, resulting in a receptor core geometry distinct from that of the G protein-bound state. Comparison with the βarr1-bound parathyroid hormone receptor 1 (PTH1R) structure further reveals both conserved and receptor-specific features of βarr1 engagement. Although outward displacement of the TM5 cytoplasmic end is observed in both PAC1R-βarr1 and PTH1R-βarr1 complexes, its specific direction and the resulting TM5-TM6 rearrangements differ between receptors, correlating with distinct βarr1 finger loop orientations within the receptor core. Together, these findings suggest that β-arrestin core engagement by class B GPCRs is accompanied by receptor-specific intracellular remodeling that may contribute to transducer selectivity in PAC1R.

Class B GPCR↗

PubMed2026

Spatial isoform sequencing at single-cell resolution reveals cell-type-specific spatial isoform variability in multiple brain cell types.

Spatial long-read technologies are increasingly common but usually lack single-cell resolution. This leaves unanswered whether spatially variable isoforms reflect variability within one cell type or differences in region-specific cell-type composition. Here, we developed Spl-ISO-Seq2 (500-nm resolution) and accompanying software, Spl-IsoQuant-2 and Spl-IsoFind, enabling long-read sequencing of >450 million barcodes versus 80,000 previously. Applying this to the adult mouse brain, we compared differential isoform abundance between known regions and spatial isoform patterns independent of predefined regions. Both identified overlapping hits, for example, Rps24 in oligodendrocytes. For known Snap25 spatial isoform variation, we show that it occurs in excitatory neurons. The region-agnostic approach also uncovered patterns missed by region-based comparisons, for example, for Ighm. Notably, many spatial isoform signals are not driven by cell-type composition alone. Finally, our software is applicable to many spatial and single-cell protocols, demonstrating reproducibility between platforms (for example, Visium HD/Stereo-seq). Overall, our experimental/analytical methods enable a submicron-resolution-isoform view and open avenues for spatial isoform disease research.

Animals↗

PubMed2026

Primate-specific regulation of the human glycosphingolipid gatekeeper UGCG.

Glycosphingolipids are essential membrane components that organize lipid microdomains and orchestrate cellular signalling, differentiation and neuronal function1-4. In humans, these functions arise from a repertoire of several hundred glycosphingolipid species generated through stepwise glycan elaboration5,6. Entry into this network is controlled by a single committed reaction catalysed by UDP-glucose ceramide glucosyltransferase (UGCG), the gatekeeper that dictates the scale and composition of glycosphingolipid diversity. Despite its biological and therapeutic importance7,8, its mechanism and regulation have remained unknown. Here we report cryogenic electron microscopy structures of full-length human UGCG in eight functional states at 2.9-3.4 Å resolution. UGCG adopts a previously unrecognized triple-pass transmembrane architecture that anchors a GT-A core at the membrane interface and creates a bipartite active site engaging soluble and membrane-embedded substrates. Contrary to canonical GT-A enzymes, UGCG uses a metal-independent catalytic mechanism driven by an arginine network. We identify a primate-specific steric element that tunes lipid affinity and catalytic turnover, modulating glycosphingolipid entry. Structures with clinically used inhibitors reveal how this architecture governs their potency and selectivity. Together, these findings define the structural and evolutionary logic by which one enzyme controls glycosphingolipid diversity and provide a framework for precision modulation of membrane lipid homeostasis in disease.

Animals↗

PubMed2006

Isotretinoin-loaded solid lipid nanoparticles with skin targeting for topical delivery.

The purpose of this study was to construct isotretinoin-loaded SLN (IT-SLN) formulation with skin targeting for topical delivery of isotretinoin. PRECIROL ATO 5 was selected as the lipid of SLN. Tween 80 and soybean lecithin were used as the surfactants to stabilize SLN. The hot homogenization method was performed to prepare the drug-loaded SLN. The various formulations were characterized by photon correlation spectroscopy and all the SLN formulations had low average size between 30 and 50 nm. Transmission electron microscopy studies showed that the IT-SLN formulation had a spherical shape. All the formulations had high entrapment efficiency ranging from 80% to 100%. The penetration of isotretinoin from the IT-SLN formulations through skins and into skins were evaluated in vitro using Franz diffusion cells fitted with rat skins. The in vitro permeation data showed that all the IT-SLN formulations can avoid the systemic uptake of isotretinoin in skins, however the control tincture had a permeation rate of 0.76+/-0.30 microg cm(-2)h(-1) through skins. The IT-SLN consisting of 3.0% PRECIROL ATO 5, 4.0% soybean lecithin and 4.5% Tween 80 could significantly increased the accumulative uptake of isotretinoin in skin and showed a significantly enhanced skin targeting effect. The studied IT-SLN showed a good stability. These results indicate that the studied IT-SLN formulation with skin targeting may be a promising carrier for topical delivery of isotretinoin.

Administration, Cutaneous↗

PubMed2006

Evaluation of the burden of logging injuries using West Virginia workers' compensation claims data from 1996 to 2001.

BACKGROUND: The risks associated with logging are well documented, however little work has been done on estimating the economic impact of injuries among loggers. METHODS: West Virginia Workers' Compensation claims data for the period 1996-2001 was used to assess the economic burden of logging injuries in the state. RESULTS: There were 1,371 claimants during this period with the highest number of claims (39%) in the 25-34 years age category. The total cost of injuries was over US dollars 14 million. The most severe injuries, traumatic brain injuries (TBI), thoracic, cervical, and lumbar, resulted in the highest medical costs, indemnity costs and permanent disability. The average medical cost for logging-related to TBI was US dollars 198,048 compared to US dollars 15,321 for other major industries. CONCLUSIONS: The magnitude of the economic costs underscores the need for active research of injury prevention among loggers and for greater attention to occupational safety and health programs.

Accidents, Occupational↗

PubMed2005

Dog sciatic nerve regeneration across a 30-mm defect bridged by a chitosan/PGA artificial nerve graft.

We have developed a dual-component artificial nerve graft comprising an outer microporous conduit of chitosan and internal oriented filaments of polyglycolic acid (PGA). The novel graft was used for bridging sciatic nerve across a 30-mm defect in six Beagle dogs, which were used as a chitosan/PGA graft group. The other Beagle dogs were divided into an autograft group (n = 6) as the positive control and a non-grafted group (n = 5) as the negative control. All animals of three groups were monitored for changes in their appearance and locomotion activities after surgery. Their posture and gait were recorded regularly with the aid of photographs and videotapes for each dog. Six months post-operatively, a combination of electrophysiological examination, FluoroGold retrograde tracing, histological assessment including light microscopy and transmission electron microscopy, immunohistochemistry as well as morphometric analyses to both regenerated nerves and target muscles was utilized to investigate the nerve repair effects of our artificial nerve graft. The results demonstrated that, in the chitosan/PGA graft group, the dog sciatic nerve trunk had been reconstructed with restoration of nerve continuity and functional recovery, and its target skeletal muscle had been re-innervated, improving locomotion activities of the operated limb. This study proves the feasibility of the chitosan/PGA artificial nerve graft for peripheral nerve regeneration by bridging a longer defect in a large animal model.

Action Potentials↗

PubMed2004

Fabrication and properties of a porous chitin/chitosan conduit for nerve regeneration.

A porous, biodegradable, natural chitin/chitosan nerve conduit was constructed. Scanning electron microscopy confirmed that it was homogeneous and highly porous. FT-IR spectra showed that there were no residues arising from the preparation process in the conduit. Addition of chitin to the chitosan solution increased the mechanical strength and maximum tensile strength from 7.2 to 9.6 MPa. Preliminary animal tests indicated that porous chitin/chitosan conduits did not swell in vivo and were compatible with surrounding tissue.

Absorbable Implants↗

PubMed2004

[A case-control study on the dietary factors of patients with acute pancreatitis].

OBJECTIVE: To explore association between dietary factor and acute pancreatitis (AP) so as to provide scientific basis for prevention of AP through healthful diet and life-style. METHODS: 100 AP patients were recruited from No. 1 Hospital affiliated to Sichuan University. Those participants in the control group 1 were from the same hospital, and those in the control group 2 were from a community. Controls were matched to cases for age (+/- 2.5) and sex. All of them were interviewed with uniform questionnaires. Conditional logistic regression was used for univariate and multivariate analysis. RESULTS: The statistic analysis indicated that AP was significantly associated with less physical activity (OR = 1.3566), obesity (OR = 3.1600), irregular eating (OR = 2.9547), engorgement after hunger (OR = 1.9603), oftentimes eating meat (OR = 1.9333), high animal oil consumption (OR = 1.5652). High rice and flour consumption (OR = 0.6724), Oftentimes drink milk (OR = 0.7154) and high milk consumption (OR = 0.4313), oftentimes eating laminavia lamx (OR = 0.5924) and green vegetable (OR = 0.3288) were inversely associated with AP. CONCLUSION: The study suggests that dietary factors may play an important role in AP.

Acute Disease↗