Objectives Loss of functional β-cell mass is a key factor contributing to poor glycemic control in advanced type 2 diabetes (T2D). We have previously reported that the inhibition of the neuropeptide Y1 receptor improves the islet transplantation outcome in type 1 diabetes (T1D). The aim of this study was to identify the pathophysiological role of the neuropeptide Y (NPY) system in human T2D and further evaluate the therapeutic potential of using the Y1 receptor antagonist BIBO3304 to improve β-cell function and survival in T2D. Methods The gene expression of the NPY system in human islets from nondiabetic subjects and subjects with T2D was determined and correlated with the stimulation index. The glucose-lowering and β-cell-protective effects of BIBO3304, a selective orally bioavailable Y1 receptor antagonist, in high-fat diet (HFD)/multiple low-dose streptozotocin (STZ)-induced and genetically obese ( db/db ) T2D mouse models were assessed. Results In this study, we identified a more than 2-fold increase in NPY1R and its ligand, NPY mRNA expression in human islets from subjects with T2D, which was significantly associated with reduced insulin secretion. Consistently, the pharmacological inhibition of Y1 receptors by BIBO3304 significantly protected β cells from dysfunction and death under multiple diabetogenic conditions in islets. In a preclinical study, we demonstrated that the inhibition of Y1 receptors by BIBO3304 led to reduced adiposity and enhanced insulin action in the skeletal muscle. Importantly, the Y1 receptor antagonist BIBO3304 treatment also improved β-cell function and preserved functional β-cell mass, thereby resulting in better glycemic control in both HFD/multiple low-dose STZ-induced and db/db T2D mice. Conclusions Our results revealed a novel causal link between increased islet NPY-Y1 receptor gene expression and β-cell dysfunction and failure in human T2D, contributing to the understanding of the pathophysiology of T2D. Furthermore, our results demonstrate that the inhibition of the Y1 receptor by BIBO3304 represents a potential β-cell-protective therapy for improving functional β-cell mass and glycemic control in T2D.

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Breast cancer is one of the commonest cancers among women. Conventional therapies cause adverse side effects in patients. Cytokine immunotherapy such as has been sought as an alternative cancer treatment in recent years. has been shown to improve anticancer immunity and anti-angiogenesis in cancers, however, its effect on apoptotic and anti-apoptotic gene expression especially in breast cancers is yet to be explored. Cytotoxicity of and cancerous breast cell lines was first determined for 24-72 h in this study. The results indicated that IL-27 treatment did not retard 184b5 cell growth, however, did inhibit and respectively. Apoptotic (TRAIL, FADD, FAS, and anti-apoptotic (BCL-2, AKT, and COX-2) genes were then amplified from untreated (control) and treated breast cancer cells and studied. TRAIL, caspase-3, caspase-8 gene expression was significantly (p < 0.05) upregulated in treated MCF-7 (442 ng/ml) and MDA-MB-231 (457 ng/ml) cells. Expression of FADD and FAS genes was not detected in both control and treated MCF-7 and MDA-MB-231 cells. COX-2 gene was also not expressed by MCF-7 cells, but reduced significantly (p < 0.05) in treated MDA-MB-231 cells. In MDA-MB-231 cells, IL-27 treatment seemed to slightly enhance the expression of AKT and BCL-2 genes which, on the other hand, was downregulated in treated MCF-7 cells. Conclusively, IL-27 is able to inhibit breast cancer cell growth and regulate apoptotic and anti-apoptotic gene expression in breast cancer cells. Keywords: IL-27; cytokine immunotherapy; triple negative breast cancer; invasive ductal breast cancerABStRAK Kanser payu dara adalah antara kanser yang paling biasa dihidapi oleh wanita. Rawatan konvensional menyebabkan kesan sampingan teruk dalam pesakit. Imunoterapi sitokin seperti interleukin-27 (IL-27) telah digunakan sebagai rawatan alternatif sejak kebelakangan ini. IL-27 telah terbukti dapat menambah baik imuniti antikanser dan aktiviti anti-angiogenesis dalam kanser, namun kesannya pada pengekspresan gen apoptotik and anti-apoptotik terutamanya pada kanser payu dara masih belum diterokai. Dalam kajian ini, kesan sitotoksisiti IL-27 pada sel selanjar bukan kanser (184b5) dan kanser (MCF-7 dan MDA-MB-231) ditentukan pada 24-72 jam dalam kajian ini. Dapatan kajian menunjukkan rawatan IL-27 tidak menjejaskan pertumbuhan sel 184b5, namun menghalang pertumbuhan sel and FADD, FAS, caspase-3 dan caspase-8) and anti-apoptotik (BCL-2, AKT, dan COX-2) kemudiannya diamplifikasikan daripada sel kanser payu dara kawalan dan terawat serta dikaji. Pengekspresan gen TRAIL, caspase-3 dan caspase-8 telah meningkat secara signifikan (p < 0.05) dalam sel yang dirawat. Pengekspresan gen FADD dan FAS gagal dikesan dalam sel MCF-7 dan MDA-MB-231, mahupun sel kawalan atau terawat. Gen COX-2 tidak diekspreskan oleh sel MCF-7 tetapi pengekspresannya telah menurun secara signifikan (p < 0.05) dalam sel MDA-MB-231 yang dirawat. Dalam sel MDA-MB-231, rawatan IL-27 meningkatkan pengekspresan gen AKT dan BCL-2, namun pengekspresan kedua-dua gen tersebut telah menurun...

Breast cancer is one of the commonest cancers among women. Conventional therapies cause adverse side effects in patients. Cytokine immunotherapy such as interleukin-27 (IL-27) has been sought as an alternative cancer treatment in recent years. IL-27 has been shown to improve anticancer immunity and anti-angiogenesis in cancers, however, its effect on apoptotic and anti-apoptotic gene expression especially in breast cancers is yet to be explored. Cytotoxicity of IL-27 in non-cancerous (184b5) and cancerous (MCF-7 and MDA-MB-231) breast cell lines was first determined for 24-72 h in this study. The results indicated that IL-27 treatment did not retard 184b5 cell growth, however, did inhibit MCF-7 (48 h) and MDA-MB-231 (72 h) cell growth with IC 50 at 442 and 457 ng/ml, respectively. Apoptotic (TRAIL, FADD, FAS, caspase-3 and caspase-8) and anti-apoptotic (BCL-2, AKT, and COX-2) genes were then amplified from untreated (control) and treated breast cancer cells and studied. TRAIL, caspase-3, caspase-8 gene expression was significantly (p < 0.05) upregulated in treated MCF-7 (442 ng/ml) and MDA-MB-231 (457 ng/ml) cells. Expression of FADD and FAS genes was not detected in both control and treated MCF-7 and MDA-MB-231 cells. COX-2 gene was also not expressed by MCF-7 cells, but reduced significantly (p < 0.05) in treated MDA-MB-231 cells. In MDA-MB-231 cells, IL-27 treatment seemed to slightly enhance the expression of AKT and BCL-2 genes which, on the other hand, was downregulated in treated MCF-7 cells. Conclusively, IL-27 is able to inhibit breast cancer cell growth and regulate apoptotic and anti-apoptotic gene expression in breast cancer cells.

Cancer immunotherapy using cytokines has been sought as an alternative therapeutic approach for treating cancers. Besides remarkable immunoregulatory properties, interleukin (IL)-27 has recently been shown to possess promising anticancer functions; hence, its potential roles in cancer immunotherapy. Although proven to be effective against cancer cell growth and angiogenesis, given its dual immune-regulating functions (pro-inflammatory and anti-inflammatory), the use of IL-27 as a cancer immunotherapeutic cytokine could possibly be a two-edged sword without meticulous and thorough research. This mini-review mainly discusses the functions and future prospects of IL-27 as an effective anticancer cytokine. Hopefully, it imparts useful insights into the potential applications of IL-27 in cancer immunotherapy