No abstract

Dysfunction of β-cells is a major characteristic in the pathogenesis of type 2 diabetes mellitus (T2DM). The combination of obesity and T2DM is associated with elevated plasma free fatty acids (FFAs). However, molecular mechanisms linking FFAs to β-cell dysfunction remain poorly understood. In the present study, we identified that the major endoplasmic reticulum stress (ERS) marker, Grp78 and ERS-induced apoptotic factor, CHOP, were time-dependently increased by exposure of β-TC3 cells to FFA. The expression of ATF6 and the phosphorylation levels of PERK and IRE1, which trigger ERS signaling, markedly increased after FFA treatments. FFA treatments increased cell apoptosis by inducing ERS in β-TC3 cells. We also found that FFA-induced ERS was mediated by the store-operated Ca2+ entry through promoting the association of STIM1 and Orai1. Moreover, calpain-2 was required for FFA-induced expression of CHOP and activation of caspase-12 and caspase-3, thus promoting cell apoptosis in β-TC3 cells. Together, these results reveal pivotal roles for Ca2+/calpain-2 pathways in modulating FFA-induced β-TC3 cell ERS and apoptosis.

Intervertebral disc degeneration (IDD) is widely considered to be one of the main causes of lower back pain, which is a chronic progressive disease closely related to inflammation, nucleus pulposus (NP) cell apoptosis and extracellular matrix (ECM) degradation. Berberine (BBR) is an alkaloid compound with an anti-inflammatory effect and has been reported to exert therapeutic action in several inflammatory diseases, including osteoarthritis. Therefore, it was hypothesized that BBR may have a therapeutic effect on IDD through inhibition of the inflammatory response. The aim of the present study was to evaluate the influence of BBR on IDD in interleukin (IL)-1β-treated human NP cells in vitro. The results showed that BBR attenuated the upregulation of ECM-catabolic factors [matrix metalloproteinase (MMP)-3, MMP-13, a disintegrin and metalloproteinase with thrombospondin motif (ADAMTS)-4 and ADAMTS-5], and the downregulation of ECM-anabolic factors (type II collagen and aggrecan) following stimulation of the human NP cells with IL-1β. Treatment with BBR also protected human NP cells from IL-1β-induced apoptosis, as determined by western blotting and flow cytometry. Mechanistically, the IL-1β-stimulated degradation of IκBα, and the phosphorylation and translocation of nuclear factor (NF)-κB p65 were found to be attenuated by BBR, indicating that NF-κB pathway activation was suppressed by BBR in the IL-1β-treated human NP cells. The results of the experiments revealed a therapeutic potential of BBR for the prevention or treatment of IDD.

IgG4-related disease is a recently proposed clinical entity with several unique clinicopathological features. A chronic inflammatory state with marked fibrosis, which can often be mistaken for malignancy, especially by clinical imaging analyses, unifies these features. In the present report, we describe a case of IgG4-producing mucosa-associated lymphoid tissue lymphoma mimicking IgG4-related disease. The patient was a 55-year-old male who was being followed for right orbital tumor over 1.5 years. The lesion had recently increased in size, so a biopsy was performed. Histologically, the lesion was consistent with IgG4-related disease ; however, IgG4⁺ plasma cells showed immunoglobulin light-chain restriction and immunoglobulin heavy chain gene rearrangement was detected in the lesion. Therefore, the lesion was diagnosed as IgG4-producing mucosa-associated lymphoid tissue lymphoma. In conclusion, in histological diagnosis of IgG4-related disease, it is important to examine not only IgG4-immunostain but also immunoglobulin light-chain restriction.