Biomedical subjects

Wei Shi

Publications and source records attributed to Wei Shi.

4 recordsLinked to original sources

PubMed2026

Calcium-Sensing Receptor Activation Disrupts Phosphatidylserine Asymmetry and Promotes Calcium Oxalate Crystal-Induced Epithelial Injury in Renal Tubular Epithelial Cells.

BACKGROUND: Calcium oxalate (CaOx) crystal retention on the renal tubular epithelium is a key step in urolithiasis. Phosphatidylserine (PS) exposure may facilitate crystal-cell adhesion, but the upstream signaling mechanisms and the relative contributions of impaired inward PS flipping versus outward PS redistribution remain unclear. MATERIALS AND METHODS: Global proteomic profiling using 2-dimensional electrophoresis and matrix-assisted laser desorption/ionization time-of-flight/time-of-flight mass spectrometry (2-DE/MALDI-TOF/TOF) in an immortalized human proximal tubular epithelial cell line (HK-2) cells exposed to calcium oxalate monohydrate (COM) identified upregulation of the calcium-sensing receptor (CaSR). HK-2 cells were treated with COM with or without the CaSR antagonist NPS2390 or the CaSR agonist gadolinium chloride (GdCl3). Bidirectional PS transport was assessed using an N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl) (NBD)-labeled phosphatidylserine (NBD-PS) fluorescence-quenching assay, and surface PS exposure was measured by annexin V binding. Aminophospholipid translocase (APLT) expression, APLT-dependent inward PS transport, crystal adhesion, oxidative stress, and apoptosis-related signaling were evaluated. RESULTS: COM increased CaSR expression, enhanced surface PS exposure, and promoted crystal adhesion with concurrent oxidative stress and apoptosis-related signaling. COM induced a CaSR-sensitive defect in APLT-dependent inward PS flipping: NPS2390 partially restored inward PS transport and APLT expression, whereas GdCl3 exacerbated these changes. In contrast, COM-enhanced outward PS redistribution and externalization was largely unaffected by CaSR modulation, indicating relative CaSR insensitivity of the outward process. Consistently, CaSR activation aggravated, while CaSR inhibition attenuated, crystal adhesion and injury-related readouts. CONCLUSIONS: COM was associated with enhanced crystal-cell adhesion, CaSR activation, and a CaSR-sensitive impairment of APLT-dependent inward PS flipping, whereas enhanced outward PS redistribution appeared largely CaSR-insensitive. Pharmacologic inhibition of CaSR attenuated epithelial injury and crystal retention-related readouts, suggesting that CaSR may represent a potential therapeutic target.

Receptors, Calcium-Sensing↗

PubMed2026

Systemic Proteomic Alterations and Predictive Biomarkers of Paroxetine Response in Refractory Rosacea: A Secondary Analysis of a Randomized Clinical Trial.

IMPORTANCE: Rosacea is a chronic inflammatory cutaneous disorder characterized by persistent erythema and vascular dysregulation. While paroxetine has shown clinical efficacy in reducing these symptoms, the systemic molecular mechanisms underlying its therapeutic response remain poorly characterized. OBJECTIVE: To investigate systemic proteomic alterations and identify potential predictive biomarkers in patients with refractory erythematous rosacea following paroxetine treatment. DESIGN, SETTING, AND PARTICIPANTS: This prospective plasma proteomic analysis was nested within a multicenter, randomized, double-blind, placebo-controlled clinical trial (Prospective Rosacea Refractory Erythema Randomized Clinical Trial [PRRERCT]). Participants included patients aged 18 to 65 years with refractory rosacea (Clinician's Erythema Assessment [CEA] score ≥3). Plasma samples were collected at baseline and after 12 weeks of treatment. The data for this study were analyzed between September 2025 and November 2025. INTERVENTIONS: Participants received oral paroxetine, 25 mg per day, for a 12-week treatment period. MAIN OUTCOMES AND MEASURES: Systemic protein expression profiles were analyzed using data-independent acquisition liquid chromatography-tandem mass spectrometry. Clinical response was evaluated using CEA and the Flushing Assessment Tool. Correlations between proteomic changes and clinical improvements were assessed, and predictive biomarkers were identified using receiver operating characteristic curve analysis. RESULTS: Among 24 participants (mean [SD] age, 35 [11] years; 24 [100%] female), paroxetine treatment significantly reduced mean (SD) CEA scores from 3.1 (0.3) to 2.3 (0.7) and Flushing Assessment Tool scores from 3.1 (0.6) to 2.0 (0.9) (P < .001). Exploratory proteomic analysis revealed 497 candidate differentially expressed proteins after treatment. Downregulated proteins showed preliminary enrichment in pathways related to immune response activation, insulin receptor signaling, and neuronal remodeling. A subset of 98 reversed-response proteins was observed, primarily linked to synaptic vesicle cycles and vascular smooth muscle contraction. Proteomic alterations were associated with clinical improvement (65 proteins for erythema; 73 for flushing). Candidate biomarkers, notably OLFML3 (area under the receiver operating characteristic curve [AUC], 0.87 [95% CI, 0.70-1.00]) and IGFBP2 (AUC, 0.80 [95% CI 0.55-1.00]), demonstrated high predictive value for clinical response. CONCLUSIONS AND RELEVANCE: In this secondary analysis of a randomized clinical trial, paroxetine treatment was associated with modulation of systemic neuro-vascular-immune networks in patients with rosacea. These exploratory findings provide preliminary mechanistic clues regarding the possible disease-modifying potential of paroxetine and point to circulating protein signatures that may facilitate personalized therapeutic strategies for rosacea management. TRIAL REGISTRATION: Chinese Clinical Trial Registry Identifier: ChiCTR2000031479.

Humans↗

PubMed2026

Deciphering the Microbiome-Gut-Eye Axis: A Mendelian Randomization Analysis of the Causal Influence of Gut Microbiota on Myopia.

INTRODUCTION: The intricate relationship between the gut microbiome and myopia is increasingly recognized, underscoring the need to explore its causal dynamics. Despite emerging evidence, the influence of Gut Microbiota (GM) on ocular development remains underexplored. METHODS: This study utilized Mendelian Randomization (MR) to investigate the causal impact of GM on the development of myopia. Instrumental variables (IVs) were identified from Genome-Wide Association Studies (GWAS), focusing on genetic variants significantly associated with microbiome composition. A comprehensive array of MR techniques was applied to ensure a robust estimation of causal effects and to adjust for potential confounders and pleiotropy. RESULTS: The Inverse-Variance Weighted (IVW) method was used to identify significant associations between GM and myopia. Increased risk of myopia was linked to the class Betaproteobacteria (OR=1.01, 95% CI 1.004-1.017, P=0.003), the order Burkholderiales (OR=1.009, 95% CI 1.001-1.016, P=0.02), the family Oxalobacteraceae (OR=1.005, 95% CI 1.001-1.01, P=0.023), and several genera including Eubacterium xylanophilum group (OR=1.007, 95% CI 1.001-1.013, P=0.033), and Bifidobacterium (OR=1.005, 95% CI 1-1.01, P=0.038). Protective effects were noted for the order Mollicutes RF9 (OR=0.994, 95% CI 0.99-0.999, P=0.014), the genus Allisonella (OR=0.996, 95% CI 0.993-0.999, P=0.019), the genus Lachnospiraceae UCG001 (OR=0.994, 95% CI 0.989-1, P=0.045), and the family Enterobacteraceae (OR=0.991, 95% CI 0.982-1, P=0.047) and order Enterobacteriales (OR=0.991, 95% CI 0.982-1, P=0.047). Sensitivity analyses further confirmed the robustness of these findings. DISCUSSION: This study provides causal evidence for the "Microbiome-Gut-Eye Axis" in myopia development, identifying specific gut microbiota that influence myopia risk. These findings suggest potential for microbiota-targeted interventions, warranting further research in diverse populations. CONCLUSIONS: The findings support the "Microbiome-Gut-Eye Axis" as a potential factor in myopia pathogenesis and highlight microbiota-targeted interventions as novel therapeutic strategies for managing myopia. This study lays the groundwork for further research on how modifying GM can influence eye health and offers new perspectives on preventive health strategies.

Humans↗

PubMed2024

A novel molecular pathway of lipid accumulation in human hepatocytes caused by PFOA and PFOS.

Exposed to ubiquitously perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) has been associated with non-alcoholic fatty liver disease (NAFLD), yet the underlying molecular mechanism remains elusive. The extrapolation of empirical studies correlating per- and polyfluoroalkyl substance (PFAS) exposure with NAFLD occurrence to real-life exposure was hindered by the limited availability of mechanistic data at environmentally relevant concentrations. Herein, a novel pathway mediating hepatocyte lipid accumulation by PFOA and PFOS at human-relevant dose (<10 μM) was identified by integrating CRISPR-Cas9 genome screening, concentration-dependent transcriptional assay in HepG2 cell and epidemiological data mining. 1) At genetic level, nudt7 showed the highest enriched potency among 569 NAFLD-related genes, and the transcription of nudt7 was significantly downregulated by PFOA and PFOS exposure (<7 μM). 2) At molecular pathway, upon exposure to ≤10-4 μM PFOA and PFOS, the downregulation of nudt7 transcriptional expression triggered the reduction of Ace-CoA hydrolase activity. 3) At cellular level, increased lipids were measured in HepG2 cells with PFOA and PFOS (<2 μM). Overall, we identified a novel mechanism mediated by transcriptional downregulation of nudt7 gene in hepatocellular lipid increase treated with PFOA and PFOS, which could potentially explain the NAFLD occurrence associated with exposure to PFASs in humans.

Humans↗