Distinct anti-inflammatory properties of alpha1-antitrypsin and corticosteroids reveal unique underlying mechanisms of action.

Alpha1-antitrypsin (AAT) is a serum protease inhibitor that rises during inflammation and healthy pregnancies. Plasma-derived AAT, indicated for genetic AAT deficiency, is presently being explored for additional medical indications. Unlike corticosteroids, some anti-inflammatory activities of AAT involve NF-κB-dependent outcomes, e.g., induction of IL-1R antagonist. AAT activities were compared to dexamethasone (DEX), using various in-vitro cells assays, animal studies, and NF-κB-p65 localization and activity studies. Results demonstrate a cytokine shift towards resolution in AAT-treated cells, as opposed to pan-suppression in DEX-treated cells. AAT enhanced, while DEX suppressed LPS-induced IL-1Ra production and re-epithelialization. When drugs were combined, AAT allowed the immunosuppressive DEX activities, while DEX at medium to high levels antagonized beneficial AAT effects. Interestingly, lower levels of DEX maintained the immunosuppressive effect, while allowing upregulation of IL-1Ra. Therefore, AAT may represent a distinct endogenous anti-inflammatory, resolution-promoting agent that may improve tissue well-being while preventing undesired corticostroids side effects.

Studies of advanced glycation end products and oxidation biomarkers for type 2 diabetes.

Advanced glycation end products (AGEs) are formed upon nonenzymatic reactions of sugars or their metabolites with proteins and other cellular constituents. Many AGEs are long lived. Recent findings suggest that AGEs may predict diabetes and its complications and thus may warrant further study. The objective of this study was to assess the validity of our experimental procedures for measuring AGEs in stored blood sample and to conduct a pilot study for developing AGE biomarkers for diabetes and/or age-related changes of glucose metabolism. We conducted a reliability study of the samples and methods using liquid chromatography-tandem mass spectrometry (LC-MS)/MS assays for 10 AGEs (including methylglyoxal-derived hydroimidazolone (MG-H1), glucosepane (GSP) and two oxidation measures, in stored repository blood samples from the Nurses' Health Study and the Health Professionals Follow-up Study. We also analyzed data relating blood GSP levels to type 2 diabetes status in a case-control study (25 cases and 15 controls). Among the AGEs, GSP, and MG-H1 showed the highest reliability across the various measures: reliability in duplicate samples and stability with delayed processing and storage over 1-2 year period. Furthermore, plasma GSP was associated with older age (P = 0.04) and type 2 diabetes status (age-adjusted P = 0.0475). Our findings suggest that analysis of these AGEs may be developed as biomarkers for diabetes and/or age-related changes of glucose metabolism. © 2018 BioFactors, 44(3):281-288, 2018.

Mechanistic evidence in support of alpha1-antitrypsin as a therapeutic approach for type 1 diabetes.

Utilizing endogenous molecules as a therapeutic approach is almost unequivocally superior to engineered or synthetic molecules. However, one rarely encounters an anti-inflammatory, cytoprotective, immunomodulatory and wound-healing molecule that has been available for use for decades. α1-antitrypsin (AAT), a circulating protein that rises more than 4-fold during acute-phase responses, has been administered for a rare genetic deficiency at large doses, for life. Aside from advances in insulin therapy, medical research in type 1 diabetes (T1D) has predominantly focused on autoimmunity--controlling the adaptive immune response. However, it is now appreciated that one may need to extend therapeutic targets to incorporate immune responses to cellular injury, as well as promote selective control over excessive inflammation and early tissue repair. Recent data suggest that tissue damage related to lung and renal ischemia-reperfusion injury, stroke, and ischemic heart disease is markedly reduced by AAT. AAT was also shown to protect pancreatic islet ß cells at multiple levels. Unlike classic immunosuppressive and anti-inflammatory approaches, AAT exerts some antiviral and antibacterial activities. Based on these and other reports, AAT is under evaluation for treatment of T1D patients in multiple clinical trials. Initial results suggest that AAT therapy could potentially improve insulin production without adverse effects. Up to 50% of individuals displayed improved islet function. It is a rare occurrence in T1D research that a therapy is offered that holds a safety profile equal or superior to that of insulin alone. While placebo-controlled trials are ongoing, the mechanism(s) behind these favorable activities of AAT are still being explored.