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Thymus and activation-regulated chemokine (TARC) is expressed on Reed-Sternberg cells of patients with classical Hodgkin lymphoma (HL) and may serve as a marker in response assessment. In our study, we correlated serum TARC levels with early response to treatment measured by PET/CT in 19 newly diagnosed patients with HL who received ABVD (Adriblastin, Bleomycin, Vinblastine, Dacarbazine) regimen. Finally, 17 patients were analyzed and six of them (35%) achieved PET/CT negativity defined as Deauville (D) 1 or 2 after 2 cycles of ABVD; 11 pts (65%) had D3 on PET/CT. None of the patients presented D 4/5. Median serum TARC levels at diagnosis were significantly higher when compared with healthy controls: 5718 pg/ml vs 76.1 pg/ml (p< 0.001). All study patients were treated with ABVD regimen and there was a significant decrease of baseline serum TARC levels after 2 cycles of therapy. No significant difference of baseline serum TARC levels was demonstrated between patients with D1/2 and D3 whereas levels were significantly decreased after 2 cycles of ABVD in patients D1/2 vs D3; p= 0.049. There was a tendency to higher baseline serum TARC levels in patients with an increased LDH (lactate dehydrogenase) activity (p= 0.08) and in those who progressed when compared with those who maintained response (p= 0.09). Serum TARC levels decrease after chemotherapy and may serve as a marker of response assessment.

•Exenatide decreases DPP-4 activity in TNF-α activated retinal pigment epithelium.•Exenatide modulates metalloproteinases involved in ECM remodeling in HRPE cells.•Exenatide reversed TNF-α-induced Akt phosphorylation at Serine 473.

Background: Diabetic retinopathy (DR) is one of the most common complications of diabetes and the leading cause of acquired blindness in adults. In diabetic patients hyperglycemia induces complex metabolic abnormalities affecting retinal homeostasis, and promotes retinal inflammation and angiogenesis. Incretin mimetic drugs such exenatide, are a relatively new group of drugs used in the treatment of diabetes. We investigated the potential direct effects of exenatide on human retinal pigment epithelium (HRPE). Methods: cAMP production was measured after stimulation of HRPE cells with GLP-1 and exenatide. Intracellular signaling pathways were also examined. HRPE cells were stimulated with TNF-a and subsequently incubated with exenatide. The concentration of metalloproteinases, MMP-1, MMP-2 and MMP-9, and tissue inhibitors of metalloproteinases, TIMP-1, TIMP-2, and TIMP-3 were evaluated. Viability, cytotoxicity and caspase 3/7 activation were determined. Activity of dipeptidyl peptidase-4 (DPP-4), an enzyme involved in GLP-1 inactivation, was also determined. Results: Both GLP-1 and exenatide stimulation in HRPE cells caused no effect in cAMP levels suggesting alternative signaling pathways. Signaling pathway analysis showed that exenatide reduced phosphorylation of Akt-Ser473, PRAS40, SAPK/JNK, Bad, and S6 proteins but not Akt-Thr308. Exenatide also decreased MMP-1, MMP-9, and TIMP-2 protein levels whereas MMP-2 level in HRPE cells was increased. Finally, we show that exenatide decreased the activity of DPP-4 in TNF-a stimulated HRPE cells. Conclusions: These findings indicate that exenatide modulates regulation of extracellular matrix components involved in retinal remodeling.

Incretin analogue drugs, a FDA-approved treatment in diabetes, has been tested for its therapeutic properties as modulators of atherosclerosis. We investigated the effects of incretin drugs on the modulation of gene expression and protein levels of matrix metalloproteinases (MMPs) as well as their inhibitors − tissue inhibitors of metalloproteinases (TIMPs) in coronary artery smooth muscle cells (hCASMC) in the context of atherosclerotic plaque formation and inflammation.

Background: Incretin analogue drugs, a FDA-approved treatment in diabetes, has been tested for its therapeutic properties as modulators of atherosclerosis. We investigated the effects of incretin drugs on the modulation of gene expression and protein levels of matrix metalloproteinases (MMPs) as well as their inhibitors — tissue inhibitors of metalloproteinases (TIMPs) in coronary artery smooth muscle cells (hCASMC) in the context of atherosclerotic plaque formation and inflammation. Methods: TNFa-stimulated hCASMC were treated with Glucagon-like Peptide 1 (GLP-1) (10 nM and 100 nM) and Exendin-4 (1 nM and 10 nM). Messenger RNA (mRNA) levels and protein concentrations of MMP-1, MMP-2, MMP-9 and TIMP-1, TIMP-2 were measured and the effects on extracellular matrix turnover under TNFa-mediated microenvironment were evaluated. Intracellular signaling pathways were also examined. Results: Our experiments reveal that GLP-1 receptor agonists downregulate the expression of MMP-1, MMP-2, MMP-9 in hCASMC under TNFa mediated inflammatory conditions. Signaling pathway analysis show that GLP-1 receptor agonists induced inhibition of AKT-Thr308 phosphorylation, PRAS40 and S6 proteins but not AKT-Ser473. Conclusions: These findings indicate that GLP-1 receptor agonists modulate the expression of MMPs through inhibition of AKT-Thr308 phosphorylation in hCASMC. These results suggest a possible role of incretin analogue drugs in therapy of coronary atherosclerosis.

Diabetes and cancer are prevalent diseases whose incidence is increasing globally. Diabetic women have a moderate risk increase in ovarian cancer, suggested to be due to an interaction between these two disorders. Furthermore, patients manifesting both diseases have associated worse prognosis, reduced survival and shorter relapse-free survival. According to current recommendations, incretin drugs such as Exenatide, a synthetic analog of Exendin-4, and Liraglutide are used as therapy for the type 2 diabetes (T2D). We studied the effects of GLP-1 and Exendin-4 on migration, apoptosis and metalloproteinase production in two human ovarian cancer cells (SKOV-3 and CAOV-3). Exendin-4 inhibited migration and promoted apoptosis through caspase 3/7 activation. Exendin-4 also modulated the expression of key metalloproteinases (MMP-2 and MMP-9) and their inhibitors (TIMP-1 and TIMP-2). Vascular endothelial cells, which contribute to the formation and progression of metastasis, were also analyzed. TNF-α-stimulated endothelial cells from iliac artery after Exendin-4 treatment showed reduced production of adhesion molecules (ICAM-1 and VCAM-1). Additionally, incretin treatment inhibited activation of apoptosis in TNF-α-stimulated endothelial cells. In the same experiment, MMPs (MMP-1 and MMP-9), which are relevant for tumor development, were also reduced. Our study demonstrated that incretin drugs may reduce cancer cell proliferation and dissemination potential, hence limiting the risk of metastasis in epithelial ovarian cancer.

There have been a number of beneficial effects of incretin agonists on the cardiovascular system. Glycated albumin (GA) and tumor necrosis factor (TNFα) may lead to endothelial dysfunction. Due to reports of cardioprotective effects of incretin agonist, we wanted to determine if GLP-1 and exendin-4 can reverse diminished production of nitric oxide (NO) after treatment with TNFα and GA. The objective of our experiment was to study the interaction between incretin agonists and proinflammatory substances like TNFα and GA on production of NO in HCAEC.

Background: There have been a number of beneficial effects of incretin agonists on the cardiovascular system. Glycated albumin (GA) and tumor necrosis factor (TNFa) may lead to endothelial dysfunction. Due to reports of cardioprotective effects of incretin agonist, we wanted to determine if GLP-1 and exendin-4 can reverse diminished production of nitric oxide (NO) after treatment with TNFa and GA. The objective of our experiment was to study the interaction between incretin agonists and proinflammatory substances like TNFa and GA on production of NO in HCAEC. Methods: Human vascular endothelial cells from the coronary artery (HCAEC) were used. The mRNA expression and protein level of endothelial nitric oxide synthase (eNOS) and inducible (iNOS) were quantified. NO production was measured in cells using DAF-FM/DA and flow cytometry. Results: TNFa (10 ng/mL) decreased eNOS: mRNA by 90% and protein level by 31%. TNFa also decreased NO by 33%. GA (500 µg/mL) neither affected eNOS expression nor the protein level, but inhibited nearly all formation of NO in endothelium. GLP-1 (100 nM) and exendin-4 (1 and 10 nM) decreased the amount of NO compared to control. Incubation of HCAEC with TNFa and incretin agonists did not change or moderately reduce the amount of NO compared to TNFa alone. Conclusions: TNFa and GA decrease production of NO in HCAEC, presumably by inducing reactive oxygen species or eNOS uncoupling. Incretin agonists in tested concentrations in the presence of l-arginine were not able to reverse this effect and instead led to a further reduction in NO production.

Advanced glycation end products (AGEs) take part in the development of diabetic retinopathy. Hyperglycemia triggers an inflammatory response in the retina. These mechanisms may lead to an enhanced expression of adhesion molecules (ICAM-1 and VCAM-1) in human retinal pigment epithelium (HRPE). Glucagon-like peptide 1 (GLP-1) functions as an incretin hormone with antidiabetogenic properties. GLP-1 also possesses vasoprotective properties.

Background: Advanced glycation end products (AGEs) take part in the development of diabetic retinopathy. Hyperglycemia trig-gersaninflammatory response inthe retina. These mechanisms may lead toanenhanced expression ofadhesion molecules (ICAM-1 and VCAM-1) in human retinal pigment epithelium (HRPE). Glucagon-like peptide 1 (GLP-1) functions as an incretin hormone with antidiabetogenic properties. GLP-1 also possesses vasoprotective properties. Methods: The aim of our study was to evaluate the influence of glycated albumin (GlyAlb; 100; 500 and 1000 mg/l) and proinflammatory cytokine, TNF-a (2.5 and 10 ng/ml), on expression of RAGE, ICAM-1 and VCAM-1 and to evaluate the influence of GLP-1 (100 nM) and its analogue, exendin-4 (10 nM), on the expression of RAGE, ICAM-1 and VCAM-1 in stimulated HRPE. Results: TNF-a increased RAGE expression in HRPE cells. The addition of GlyAlb (500 and 1000 mg/l) resulted in a decrease of RAGE expression. Both TNF-a and GlyAlb increased the secretion of both adhesion molecules. In cells co-treated with GLP-1 or exendin-4 both incretins decreased RAGE expression in TNF-a treated cells, and in GlyAlb group. The ICAM-1 expression was lowered by exendin-4 and GLP-1 in cells stimulated by TNF-a and GlyAlb. The similar results were obtained for VCAM-1. All observed alterations were statistically significant. Conclusions: The obtained results indicate that both GLP-1 and exendin-4 by decreasing the expression of RAGE in HRPE can make these cells more resistant to circulating AGEs, and decreased expression of circulating VCAM-1 and ICAM-1, can be the result of anti-inflammatory properties of incretins and decreased expression of RAGE.

Soluble cell adhesion molecules (sCAMs) are involved in the development of neoplastic diseases. sCAMs can block lymphocytes and promote angiogenesis and migration of breast cancer (BC) cells. Interleukin 6 (IL-6) and tumor necrosis factor α (TNF-α) enhance metastatic potential via upregulation of CAMs. We assessed soluble interleukin-6 receptor subunit alpha (IL-6Ra), TNF-R1, TNF-R2, E-selectin, P-selectin, VCAM-1, ICAM-1, and EpCAM in 89 women with stage I–III BC and 28 healthy women. Blood samples were obtained at the beginning of neoadjuvant/induction (N= 49) or adjuvant treatment (N= 40), and after 2 months. Surgery revealed complete response in 29.4% of patients, partial response in 67%, and stable disease in 5.9%. Achieving a pathological response was 4 times greater for baseline levels of sIL-6Ra >5.63 ng/mL [odds ratio (OR) = 4.1, 95% confidence interval (CI): 0.8–20.4, P= 0.08] and more than 6 times for soluble tumor necrosis factor receptor 1 (sTNF-R1) ≥ 0.97 ng/mL (OR = 6.2, 95% CI: 1.2–32.3, P< 0.05). Compared with the control group, serum sP-selectin, soluble epithelial cell adhesion molecule (sEpCAM), and sTNF-R2 concentrations were significantly higher in patients who started adjuvant therapy (P< 0.05) and preoperative therapy (P< 0.01). Baseline serum sIL-6Ra concentrations were significantly higher in patients before surgery than in patients after tumor resection (P< 0.05), independent of the follow-up time. The baseline serum soluble receptors of IL-6 (sIL-6R) and TNF-α (sTNF-R1) concentrations have a predictive value for preoperative therapy in patients with BC.

Cardiovascular disease is the main cause of mortality and morbidity in the industrialized world. Incretin‐mimetic compounds such as exenatide are currently used in the treatment of type 2 diabetes. We investigated the effects of incretin drugs on apoptosis, adhesion molecule expression, and concentration of extracellular matrix (ECM) metalloproteinases under inflammatory conditions within the context of atherosclerotic plaque formation of both human coronary artery endothelial cells (hCAECs) and human aortic endothelial cells (hAoECs). TNF‐α‐stimulated hCAECand hAoECwere treated with exenatide (1 and 10 nmol/L) and GLP‐1 (10 and 100 nmol/L) then evaluated for caspase 3/7 activity and assayed for protein levels of adhesion molecules sICAM‐1, sVCAM‐1, and P‐selectin. Concentrations of matrix metalloproteinases (MMPs) MMP‐1, MMP‐2, MMP‐9, and their inhibitors—tissue inhibitor of metalloproteinases (TIMPs), TIMP‐1, TIMP‐2 were also measured to evaluate the effects on extracellular matrix turnover within an inflammatory environment. Intracellular signaling pathways were evaluated via transfection of endothelial cells with a GFPvector under the NF‐κB promoter. Our experimental data suggest that GLP‐1 receptor (GLP‐1R) agonists downregulate activation of NF‐κB and adhesion molecules ICAMand VCAM, but not P‐selectin, in both endothelial cell lines. Exendin‐4 and GLP‐1 modulate the expression of MMPs and TIMPs, with statistically significant effects observed at high concentrations of both incretins. Expressive modulation may be mediated by NF‐κB as observed by activation of the vector when stimulated under inflammatory conditions. These findings indicate that GLP‐1 analogs have anti‐inflammatory properties in endothelial cells that may play an important role in preventing atherosclerosis.