Adiponectin predominantly secreted from adipose tissue has exhibited potent anti-proliferative properties in cancer cells via modulating cell cycle and apoptosis. FoxO3A, a Forkhead box O member of the transcription factor, plays a critical role in modulating expression of genes involved in cell death and/or survival. In this study, we investigated the role of FoxO3A signaling in anti-cancer activities of adiponectin. Herein, we have shown that treatment with globular adiponectin (gAcrp) increases p27 but decreases cyclinD1 expression in human hepatoma (HepG2) and breast (MCF-7) cancer cells. Gene ablation of FoxO3A prevented gAcrp-induced increase in p27 and decreased in cyclin D1 expression, and further ameliorated cell cycle arrest by gAcrp, indicating a critical role of FoxO3A in gAcrp-induced cell cycle arrest of cancer cells. Moreover, treatment with gAcrp also induced caspase-3/7 activation and increased Fas ligand (FasL) expression in both HepG2 and MCF-7 cells. Transfection with FoxO3A siRNA inhibited gAcrp-induced caspase-3/7 activation and FasL expression, suggesting that FoxO3A signaling also plays an important role in gAcrp-induced apoptosis of cancer cells. We also found that gene silencing of AMPK prevented gAcrp-induced nuclear translocation of FoxO3A in HepG2 and MCF-7 cells. In addition, suppression of AMPK also blocked gAcrp-induced cell cycle arrest and further attenuated gAcrp-induced caspase-3/7 activation, indicating that AMPK signaling plays a pivotal role in both gAcrp-induced cell cycle arrest and apoptosis via acting as an upstream signaling of FoxO3A. Taken together, our findings demonstrated that AMPK/FoxO3A axis plays a cardinal role in anti-proliferative effect of adiponectin in cancer cells.

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Loss of the epithelial intermediate filament protein keratin 8 (K8) in murine β cells leads to irregular insulin vesicles and decreased insulin levels. Because mitochondria are central in glucose-stimulated insulin secretion, the relationship between keratins and β-cell mitochondrial function and morphology was investigated. β cells in murine K8-knockout (K8) islets of Langerhans have increased numbers of mitochondria, which are rounder and have diffuse cristae, as seen by electron microscopy. The mitochondrial network in primary cultured K8 β cells is more fragmented compared with K8 mitochondria, correlating with decreased levels of mitofusin 2 and the mitofusin 2- and keratin-binding protein trichoplein. K8 β-cell mitochondria have decreased levels of total and mitochondrial cytochrome , which correlates with a reduction in electron transport complexes I and IV. This provokes loss of mitochondrial membrane potential and reduction of ATP and insulin amount, as seen in K8 β cells. Mitochondria in K8 wild-type β cells and MIN6 insulinoma cells overexpressing K8 and 18 are more stationary compared with mitochondria in keratin-deficient cells. In conclusion, keratins, likely through trichoplein-mitofusin interactions, regulate both structural and dynamic functions of β-cell mitochondria, which could have implications for downstream insulin secretion.-Silvander, J. S. G., Kvarnström, S. M., Kumari-Ilieva, A., Shrestha, A., Alam, C. M., Toivola, D. M. Keratins regulate β-cell mitochondrial morphology, motility, and homeostasis.

Steroid receptor coactivator-3 (SRC-3) regulates the activity of both nuclear hormone receptors and a number of key transcription factors. It is implicated in the regulation of cell proliferation, inflammation and in the progression of several common cancers including breast, colorectal and lung tumors. Phosphorylation is an important regulatory event controlling the activities of SRC-3. Serine 857 is the most studied phospho-acceptor site, and its modification has been reported to be important for SRC-3-dependent tumor progression. In this study, we show that the stress-responsive p38 MApK-MK2 signaling pathway controls the phosphorylation of SRC-3 at S857 in a wide range of human cancer cells. Activation of the p38 MApK-MK2 pathway results in the nuclear translocation of SRC-3, where it contributes to the transactivation of NF-kB and thus regulation of IL-6 transcription. The identification of the p38 MApK-MK2 signaling axis as a key regulator of SRC-3 phosphorylation and activity opens up new possibilities for the development and testing of novel therapeutic strategies to control both proliferative and metastatic tumor growth. The steroid receptor coactivator 3 (SRC-3) is a transcriptional coactivator of the p160 family encoded by the gene nuclear receptor coactivator 3 (NCOA3). It was originally identified as a coactivator for nuclear receptors 1 , but is now recognized as a coactivator of several other transcription factors including E2F transcription factor 1 (E2F1) 2 , polyomavirus enhancer activator 3 (PEA3) 3 , activator protein-1 (AP-1) 4,5 , and nuclear factor-κB (NF-κB) 6,7. Based on this broad spectrum of transcriptional activities, SRC-3 has been shown to play important roles in a wide range of physiological processes, such as cell proliferation, cell survival, mammary gland development 8 and metabolism 9. Since 1997, when SRC-3 was found to be amplified in breast cancer 10 its role in cancer progression has been broadly investigated. It has been shown to be implicated in hormone-related cancers, such as endometrial 11 , ovarian 12 , prostate 13 and breast cancer 14 , but also in in hormone-independent cancer types such as esophageal, squamous cell, colorectal, hepatocellular, pancreatic and non-small cell lung cancer 15. SRC-3 modulates various processes, for example cell proliferation 16 , development of metastasis 17 , and resistances to anti-cancer drugs 18,19. The function of the SRC-3 protein is highly regulated by post-transcriptional modifications through phosphorylation. SRC-3 is phosphorylated at multiple residues mediated by distinct protein kinases, suggesting that SRC-3 might be controlled by several different signaling pathways in health and disease 20,21. Among the different phosphorylation sites, the most frequently reported modification of SRC-3 is the phosphorylation at serine 857 (S857) 22. This phosphorylation has been shown to be important for regulation of estrogen receptor, androgen receptor and NF-κB-mediated transcription 20. In addition, more recent data indicate that phosp...

Neonatal sepsis is a common reason for neonatal morbidity and mortality. Only clinical manifestations are inadequate to diagnose neonatal sepsis. In context of Nepal, there has been few studies correlating bacterial and clinical profile but none till now has managed to define the most adequate parameters to diagnose neonatal sepsis with certainty. Hence, this study is conducted to describe and compare clinical and laboratory characteristics of culture positive and clinically suspected sepsis (blood culture negative) and then assess whether differences exist between them. A descriptive prospective study was carried out for a period of one year starting from April 2017 to March 2018 at the NICU of Kathmandu Medical College. A total of 129 culture proven and suspected septic neonates were included. Clinical features, septic screening including blood culture, biochemical tests and radiological findings were taken into consideration. The incidence of definite neonatal sepsis was 22.4%. The most common bacterial isolates were gram negative bacteria. Klebsiella spp (48%) followed by CoNS (17%), Acinetobacter spp (14%), Enterobacter spp (7%), Pseudomonas (7%) and Staphylococcus aureus (7%) were isolated. Different non specific clinical features like respiratory and gastro-intestinal symptoms were seen. The neonates with clinical features had positive correlation with abnormal laboratory parameters with statistically significant p value, suggesting that septic neonates showed abnormal laboratory parameters. This data emphasizes the role of laboratory parameters other than blood culture for the diagnosis and empirical treatment of neonatal sepsis.