Resveratrol mitigates pancreatic TF activation and autophagy-mediated beta cell death via inhibition of CXCL16/ox-LDL pathway: A novel protective mechanism against type 1 diabetes mellitus in mice.

The role of CXC chemokine ligand 16 (CXCL16), oxidized LDL (ox-LDL), tissue factor (TF) and autophagy-induced beta cell death in type 1 diabetes mellitus (T1DM) pathogenesis is still unclear. We examined the therapeutic potential and mechanism of resveratrol (RES) against T1DM. Diabetes was induced in Balb/c mice by i. p. injection of 55 mg/kg streptozotocin (STZ) for five consecutive days. The control group received vehicles. RES or (RES + STZ) groups received RES (50 mg/kg, i. p.) daily for 12 days starting from the fourth day of buffer or STZ injections, respectively. Blood glucose, serum insulin, beta cell mass, serum lipid profiles, histological changes, oxidative stress biomarkers were determined. Moreover, CXCL16, TF, ox-LDL, P62 and LC3 tissue expression were also analyzed. Diabetic mice showed a marked deterioration in biochemical, physical and oxidative stress parameters. Interestingly, immunofluorescence analysis showed a remarkable elevation in CXCL16 (12 folds), ox-LDL (9 folds), TF (8.3 folds) in pancreatic B-cells. Moreover, western blotting revealed a profound increase in ox-LDL (2.6 folds), TF (3.2 folds), while a significant decline in P62 (0.34) and LC3 (0.25) when compared to control. RES mitigated biochemical, physical, oxidative imbalance and distorted pancreatic architecture in T1DM mice. Intriguingly, CXCL16, ox-LDL, TF and autophagic markers were also restored after RES treatment. Our data give the first direct evidence that beta cell-specific CXCL16/ox-LDL pathway activation is a potential trigger of TF activation and autophagic beta cell death in T1DM. Moreover, RES may have potential therapeutic applications for prevention of T1DM mainly via ameliorating this pathway.

Enoxaparin prevents CXCL16/ADAM10-mediated cisplatin renal toxicity: Role of the coagulation system and the transcriptional factor NF-κB.

BACKGROUND AND AIMS: C-X-C ligand 16 (CXCL16) is an exceptional chemokine that is expressed as transmembrane and soluble forms. Our aim is to shed lights on the role of CXCL16/ADAM10 (a disintegrin and metalloproteinase) in cisplatin (CP)-induced renal toxicity as well as possible protective effect of enoxaparin. MAIN METHODS: Male albino mice were injected with CP (30 mg/kg, i.p.) in the presence or absence of enoxaparin (ENOX) (5 mg/kg, i.p.). Renal toxicity markers, serum level of cystatin-c, complete blood count (CBC), prothrombin time (Pt) and tissue expression of CXCL16, ADAM10, cluster of differentiation 3 (CD3), fibrinogen, tissue factor (TF), nuclear factor-κB (NF-κB) and tumour necrosis factor α (TNF-α) were measured. Besides, serum CXCL16 and histopathology were also analyzed. KEY FINDINGS: CP increased renal toxicity markers, renal expression of CXCL16/ADAM10, fibrinogen, TF and CD3 tissue expression in a time-dependent manner, and elevated serum cystatin-c, CXCL16 and tissue TNF-α, NF-κB. Alternatively, ENOX restored the deteriorated parameters and reduced tissue level of NF-κB. SIGNIFICANCE: This report, for the first time, showed that soluble CXCL16 resulting from ADAM10 cleavage may recruit T-cells to the renal glomeruli and tubules in CP toxicity. Furthermore, TF and fibrin, have similar expression and location pattern like CXCL16 and ADAM10 suggesting their possible interrelation. ENOX successfully restored the deteriorated parameters suggesting it may be an effective nephroprotective adjuvant therapy.