Autophagy and endoplasmic reticulum (ER) stress response is important for cancer cells to maintain malignancy and resistance to therapy. trans-Resveratrol (RSV), a non-flavonoid agent, has been shown to induce apoptosis in human nasopharyngeal carcinoma (NPC) cells. In this study, the involvements of tumor-specific ER stress and autophagy in the RSV-mediated apoptosis were investigated. In addition to traditional autophagosomes, the images of transmission electron microscopy (TEM) indicated that RSV markedly induced larger, crescent-shaped vacuoles with single-layered membranes whose the expanded cisternae contains multi-lamellar membrane structures. Prolonged exposure to RSV induced a massive accumulation of ER expansion. Using an EGFP-LC3B transfection and confocal laser microscopy approach, we found RSV-induced EGFP-LC3 puncta co-localized with ER-tracker red dye, implicating the involvement of LC3II in ER expansion. The proapoptotic effect of RSV was enhanced after suppression of autophagy by ATG7 siRNA or blocking the autophagic flux by bafilomycin A1, but that was not changed after targeted silence of IRE1 or CHOP by siRNA. Using caspase inhibitors, we demonstrated the upregulation of caspase-12 (casp12) and the activation of casp4 were associated with the proapoptotic induction of RSV through the caspase-9/caspase-3 pathway. Intriguingly, siRNA knockdown of casp12, but not caspase-4, decreased the susceptibility of the NPC cells to RSV-mediated apoptosis. Further, we showed that RSV dose-dependently increased the ceramide accumulation as assessed by LC-MS/MS system. Using serine palmitoyltransferase (SPT, a key enzyme of de novo ceramide biosynthesis) inhibitors (L-cycloserine and myriocin), we found the increased ceramide accumulation was strongly correlated with the proapoptotic potential of RSV. This study revealed the ER expansion and upregulation of ER casp12 together may indicate profound biological effects of RSV and contributed to NPC cell death. Targeting the different status of ER stress may provide a possible strategy for cancer treatments.

The liver architecture plays an important role in maintaining hemodynamic balance, but the mechanisms that underlie this role are not fully understood. Hepsin, a type II transmembrane serine protease, is predominantly expressed in the liver, but has no known physiological functions. Here, we report that hemodynamic balance in the liver is regulated through hepsin. Deletion of hepsin (hepsin 2/2 ) in mice resulted in enlarged hepatocytes and narrowed liver sinusoids. Using fluorescent microbeads and antihepsin treatment, we demonstrated that metastatic cancer cells preferentially colonized the hepsin 2/2 mouse liver as a result of the retention of tumor cells because of narrower sinusoids. The enlarged hepatocytes expressed increased levels of connexin, which resulted from defective prohepatocyte growth factor (pro-HGF) processing and decreased c-Met phosphorylation in the livers of hepsin 2/2 mice. Treatment of hepsin 2/2 mice with recombinant HGF rescued these phenotypes, and treatment of wild-type mice with an HGF antagonist recapitulated the phenotypes observed in hepsin 2/2 mice. Conclusion: Our findings show that the maintenance of hepatic structural homeostasis occurs through HGF/c-Met/connexin signaling by hepsin, and hepsin-mediated changes in liver architecture significantly enhance tumor metastasis to the liver. (HEPATOLOGY 2012;56:1913-1923 T ype II transmembrane serine proteases (TTSPs) have important physiological functions and pathological implications in iron metabolism, 1 blood pressure regulation, and metastasis of cancers. 2 More than 20 TTSPs exist and they are divided into four subfamilies. Among these families, the hepsin/ enteropeptidase subfamily is recognized structurally by a scavenger receptor cysteine-rich domain linked to a serine protease domain contained within an extracellular stem region. Although hepsin may be involved in the progression of several human cancers, 3 its physiological function has not yet been fully characterized. Hepsin is predominantly expressed in the liver. 4 Antisenseoligonucleotide blockade of hepsin affects cell growth and enlarges and flattens hepatoma cells. 5 Several in vitro studies have identified substrates for hepsin, including coagulation factor VII, 6 prohepatocyte growth factor (pro-HGF), 7 and prourokinase-type plasminogen activator. 8 In addition, hepsin colocalizes with desmoplakin at the sites of desmosomal junctions. 9

CDGSH iron–sulfur domain‐containing protein 2 (Cisd2), a protein that declines in an age‐dependent manner, mediates lifespan in mammals. Cisd2 deficiency causes accelerated aging and shortened lifespan, whereas persistent expression of Cisd2 promotes longevity in mice. Alzheimer's disease (AD) is the most prevalent form of senile dementia and is without an effective therapeutic strategy. We investigated whether Cisd2 upregulation is able to ameliorate amyloid β (Aβ) toxicity and prevent neuronal loss using an AD mouse model. Our study makes three major discoveries. First, using the AD mouse model (APP/PS1 double transgenic mice), the dosage of Cisd2 appears to modulate the severity of AD phenotypes. Cisd2 overexpression (∼two‐fold) significantly promoted survival and alleviated the pathological defects associated with AD. Conversely, Cisd2 deficiency accelerated AD pathogenesis. Secondly, Cisd2 overexpression protected against Aβ‐mediated mitochondrial damage and attenuated loss of neurons and neuronal progenitor cells. Finally, an increase in Cisd2 shifted the expression profiles of a panel of genes that are dysregulated by AD toward the patterns observed in wild‐type mice. These findings highlight Cisd2‐based therapies as a potential disease‐modifying strategy for AD. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Circulating interleukin-1beta (IL-1beta), IL-6, tumour necrosis factor-alpha (TNF-alpha), osteocalcin, and conventional parameters of inflammation were examined serially in 14 children with juvenile idiopathic arthritis (JIA) to determine any correlation with the disease activity. Serum IL-1beta was undetectable in all JIA patients. Serum IL-6, white blood cell counts, platelet counts, erythrocyte sedimentation rate and C-reactive protein levels were significantly elevated in the active phase of JIA, whereas hemoglobin levels were significantly lower. Osteocalcin levels were decreased and TNF-alpha increased in active JIA status, but these differences showed no statistical significance. We concluded that inflammatory cytokines play an important role in JIA. Monitoring IL-6 in children with JIA is useful in determining disease activity and response to therapy. These findings confirm earlier reports.