PBI-4050 Improves Metabolic Regulation and Diabetic Nephropathy through Reduction of ER Stress, Pro-Inflammatory/Fibrotic Markers, Galectin-3 Expression, and Inflammatory Cell Infiltration in ob/ob Mouse Model
Bibliographic record
Abstract
Background: PBI-4050 displays anti-inflammatory/fibrotic properties with metabolic regulation. PBI-4050 has been shown to reduce glycated hemoglobin levels, and different biomarkers related to kidney and heart injury in a phase II open label clinical trial in patients suffering from type 2 diabetes with metabolic syndrome. PBI-4050 has also completed with success an open label phase II clinical trial in patients with idiopathic pulmonary fibrosis (IPF) and in patients with Alström Syndrome. The aim of this study was to investigate the effect of PBI-4050 on diabetic nephropathy in leptin deficient ob/ob mice, a model of type 2 diabetes and metabolic syndrome. Methods: ob/ob mice were treated with vehicle or PBI-4050 (200 mg/kg, oral once a day) from day 1 to 105. OGTT, triglycerides, adiponectin and serum insulin levels, as well as inflammatory cell infiltration and pro-inflammatory/fibrotic gene expression and histology of kidney and white adipose tissue (WAT) were examined. Results: PBI-4050 improved glucose metabolism, reduced serum triglycerides and insulin levels, and increased serum adiponectin levels. In kidneys, PBI-4050 reduced ER stress (p-PERK, ATF-6, CHOP and p-IRE1). Furthermore, PBI-4050 reduced α-SMA, fibronectin and CTGF gene expression. Pro-inflammatory/remodeling markers expression (MRC-1, MCP-1 and MMP-2) were also reduced with PBI-4050 treatment. Moreover, histological analysis revealed that PBI-4050 reduced collagen deposition in glomeruli. Specific immunostaining also showed that PBI-4050 significantly reduced galectin-3 expression in kidney and WAT. Finally, PBI-4050 reduced the expression levels of inflammatory cell infiltration markers (Ly6G and F4/80) in kidney. Conclusions: These results suggest that PBI-4050 is a strong potential candidate for the treatment of metabolic diseases and related diabetic nephropathy. Disclosure J. Simard: Employee; Self; Prometic Biosciences Inc.. Stock/Shareholder; Self; Prometic Life Sciences Inc. M. Cloutier: Employee; Self; Prometic Biosciences Inc.. Stock/Shareholder; Self; Prometic Life Sciences Inc. A. Laverdure: Employee; Self; Prometic Biosciences Inc.. Stock/Shareholder; Self; Prometic Life Sciences Inc. J. Richard: Employee; Self; Prometic Biosciences Inc.. Stock/Shareholder; Self; Prometic Life Sciences Inc. L. Gervais: Employee; Self; Prometic Biosciences Inc.. Stock/Shareholder; Self; Prometic Life Sciences Inc. A. Felton: Employee; Self; Prometic Biosciences Inc.. Stock/Shareholder; Self; Prometic Life Sciences Inc. B. Grouix: Employee; Self; Prometic Biosciences Inc.. Stock/Shareholder; Self; Prometic Life Sciences Inc. P. Laurin: Employee; Self; Prometic Biosciences Inc.. Stock/Shareholder; Self; Prometic Life Sciences Inc.. Board Member; Self; Prometic Life Sciences Inc. M. Leduc: Employee; Self; Prometic Biosciences Inc.. Stock/Shareholder; Self; Prometic Life Sciences Inc. F.A. Leblond: Employee; Self; Prometic Biosciences Inc.. Stock/Shareholder; Self; Prometic Life Sciences Inc. L. Gagnon: Employee; Self; Prometic Biosciences Inc.. Stock/Shareholder; Self; Prometic Life Sciences Inc..
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".