IFNgamma-Targeted Immunosuppression in Inhibiting Features of Polycystic Ovary Syndrome (PCOS) in Mice: A Comparative Therapeutic Approach.
Bibliographic record
Abstract
Introduction: Polycystic ovary syndrome (PCOS), a major cause of anovulatory infertility, is characterized by failure of ovulation and is associated with obesity, insulin resistance and chronic inflammation. Emerging evidence suggests a role for an aberrant, IFNγ-associated autoimmune activation in aggravating clinical features of insulin resistance and PCOS. We hypothesized that IFNγ-targeted iummnosuppression benefits inhibiting the development of PCO in obesity-induced type 2 diabetic mice. Research Design: Thirty-five New Zealand Obese (NZO) female mice (Jackson's Laboratories, USA) weaned till age of 24 weeks on high-fat (HF) (60% calories/gm) (also referred to as hfd-NZO). HF-fed BALBc-Rag2/IL2-gc female mice (n= 24) (Jackson's Laboratories) were used as controls. Untreated, or those receiving three weeks of Tacrolimus (0.1mg/kg and 0.05mg/kg sq q2d), Pimecrolimus (0.1mg/kg sq q2d) and Sirolimus (0.1mg/kg sq q2d) or Metformin (2g/day ad libitum) hf-NZO were examined for features of PCOS. Materials and Methods: The following methods were used to asses benefits: (1) body mass monitoring, glucose tolerance tests (GTT), and the Homeostasis Model of Assessment (HOMA) for Insulin Resistance (HOMA-IR) and for pancreatic Beta-cell functions (HOMA-B); (2) WB to determine phosphorylation of Insulin Receptor Substrate (IRS) and Akt in the liver and skeletal muscle; (3) flow-cytometry assessing alterations in the splenic and ovarian CD4+ve, CD8a+ve, CD19+ve, F4/80+ve [single stained versus dual positive for CD206 and/or CD11c], and those expressing IFNγ, IL6 and/or IL4); (5) immunohistochemistery to localize activated ovarian macrophages, T and B-cells.Results: The administration of macrolides to the hfd-NZO female mice inhibited body mass gain, normalized GTT, suppressed high HOMA-IR and improved HOMA-B, restored ovulatory ovarian phenotype, maintained low-level expression (p < 0.01) of IFNγ and/or IL6 producing splenic and ovarian CD4+ve T, CD19+ve B-cells and F4/80+ve macrophages, and restored the phosphorylation status of hepatic and skeletal muscle IRS and Akt (p < 0.05). The expression of IL4 secreting splenic and ovarian cells varied among hfd-NZO mice and was relatively unaffected by either of the therapeutic approaches presently used. Conclusions: This study has demonstrated a detrimental role for an aberrant IFNγ signaling in the establishment of PCO in mice and presented evident benefits for the use of IFNγ-targeted immunosuppression relative to glucose intolerance and ovarian malfunctions in the obese and type 2 diabetic subjects
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 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 source (direct Gemma or distilled Codex), 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".