Kinesin-like protein KIFC1, a normally nonessential kinesin motor, plays a critical role in centrosome clustering in cancer cells and is essential for the survival of cancer cells. Herein, we reported that KIFC1 expression is up-regulated in breast cancer, particularly in estrogen receptor negative, progesterone receptor negative and triple negative breast cancer, and is not associated with epidermal growth factor receptor 2 status. In addition, KIFC1 is highly expressed in all 8 tested human breast cancer cell lines, but is absent in normal human mammary epithelial cells and weakly expressed in 2 human lung fibroblast lines. Moreover, KIFC1 silencing significantly reduced breast cancer cell viability. Finally, we found that PJ34, a potent small molecule inhibitor of poly(ADP-ribose) polymerase, suppressed KIFC1 expression and induced multipolar spindle formation in breast cancer cells, and inhibited cell viability and colony formation within the same concentration range, suggesting that KIFC1 suppression by PJ34 contributes to its anti-breast cancer activity. Together, these results suggest that KIFC1 is a novel promising therapeutic target for breast cancer.

OBJECTIVE-Lipoic acid synthase (LASY) is the enzyme that is involved in the endogenous synthesis of lipoic acid, a potent mitochondrial antioxidant. The aim of this study was to study the role of LASY in type 2 diabetes.RESEARCH DESIGN AND METHODS-We studied expression of LASY in animal models of type 2 diabetes. We also looked at regulation of LASY in vitro under conditions that exist in diabetes. Additionally, we looked at effects of LASY knockdown on cellular antioxidant status, inflammation, mitochondrial function, and insulin-stimulated glucose uptake.RESULTS-LASY expression is significantly reduced in tissues from animal models of diabetes and obesity compared with ageand sex-matched controls. In vitro, LASY mRNA levels were decreased by the proinflammatory cytokine tumor necrosis factor (TNF)-␣ and high glucose. Downregulation of the LASY gene by RNA interference (RNAi) reduced endogenous levels of lipoic acid, and the activities of critical components of the antioxidant defense network, increasing oxidative stress. Treatment with exogenous lipoic acid compensated for some of these defects. RNAi-mediated downregulation of LASY induced a significant loss of mitochondrial membrane potential and decreased insulinstimulated glucose uptake in skeletal muscle cells. In endothelial cells, downregulation of LASY aggravated the inflammatory response that manifested as an increase in both basal and TNF-␣-induced expression of the proinflammatory cytokine, monocyte chemoattractant protein-1 (MCP-1). Overexpression of the LASY gene ameliorated the inflammatory response.CONCLUSIONS-Deficiency of LASY results in an overall disturbance in the antioxidant defense network, leading to increased inflammation, insulin resistance, and mitochondrial dysfunction. Diabetes 58:600-608, 2009 T ype 2 diabetes is the most prevalent chronic metabolic disease in the world. In the past decade, considerable evidence has accumulated implicating oxidative stress as a key factor that accelerates the onset and progression of type 2 diabetes. Chronic oxidative stress causes inflammation and mitochondrial dysfunction and culminates in insulin resistance, which ultimately progresses to diabetes. Oxidative stress also promotes cellular dysfunction and damage, leading to the development of secondary complications of diabetes. The underlying cause of redox imbalance is a deficiency in the endogenous antioxidant network. This deficiency would result in an inability to combat excessive amounts of reactive oxygen species (ROS) and tip the balance in favor of oxidative stress.Redox balance is maintained by an antioxidant defense network within mitochondria, consisting of stress-responsive enzymes such as superoxide dismutase (SOD), catalase and reduced glutathione (GSH), and antioxidants. The antioxidant defense network is activated in response to excessive production of ROS in the mitochondria, thereby neutralizing the ROS before they inflict damage on cellular molecules. Lipoic acid is a potent mitochondrial antioxidant that plays a central role in...

A Bartonella henselae genomic A library was screened with antiserum generated in mice against live B. henselae. One of the immunoreactive clones expressed a 17-kDa antigen that was characterized previously as an immunodominant protein of B. henselae. Sequence analysis of the recombinant clone, pBHIM-2, revealed that the open reading frame (ORF) encoding the 17-kDa antigen was situated between homologs of virB4 and virB6, two genes that belong to the virB operon. The virB operon has been associated with the transfer of oncogenic T-DNA in Agrobacterium tumefaciens and with secretion of the pertussis toxin in Bordetella pertussis. Downstream of the virB6 gene within pBHIM-2 was a partial open reading frame that was homologous to the virB8 gene. Rescreening of the library by plaque hybridization using probes specific to the 5' and 3' ends of the pBHIM-2 insert resulted in the isolation of recombinant clones containing additional virB genes. Assembly of the sequences obtained from the recombinant clones revealed that eight of the open reading frames encode homologs of the VirB proteins. The homology and colinearity with the virB genes suggest that the gene encoding the 17-kDa antigen is expressed within the virB locus of B. henselae.

Adiponectin, a secretory protein specifically expressed by adipose tissue, has been shown to play a critical role in the maintenance of metabolic homeostasis. A deficiency of adiponectin has been linked to a wide variety of metabolic abnormalities, including obesity and associated disorders such as insulin resistance, hyperglycemia, dyslipidemia, hypertension and nonalcoholic fatty liver disease, collectively referred to as the "metabolic syndrome". Conversely, increased expression of adiponectin corrects these abnormalities, as revealed by the positive metabolic effects observed in genetic over expression studies or by administration of recombinant adiponectin. This has led to widespread interest in its role as a therapeutic target for treatment of a range of metabolic disorders such as diabetes mellitus, obesity, inflammatory and cardiovascular diseases. Various therapeutic approaches targeted at increasing adiponectin levels, or its activity, are being explored. These consist of increasing expression of adiponectin or its receptors by inducers, increasing circulating levels of adiponectin by administering recombinant protein, peptide mimetic approaches, or increasing expression/activity of its downstream effectors such as AMPK or PPAR alpha. Many of these approaches have achieved therapeutic benefits in animal models of metabolic diseases. Despite the profusion of research on adiponectin and ways to modulate it, there are limited number of studies focused on smallmolecule based-therapeutic approaches. In this review, we summarize what is currently known with respect to the therapeutic potential of adiponectin and discuss the challenges in designing small molecule-based therapies.

An extracellular particle approximately 40 nM in diameter was detected in culture supernatant from the fastidious bacterium Rochalimaea henselae. This particle has at least three associated proteins and contains 14 kbp linear DNA segments that are heterogeneous in sequence. The 14 kbp DNA was also present in R. henselae cells as an extrachromosomal element for all 14 strains tested. Despite attempts to induce lysis of R. henselae, plaque formation was not observed. A similar particle, also containing 14 kbp DNA, was observed in Bartonella bacilliformis, and may be analogous to a bacteriophage that has been described elsewhere for B. bacilliformis.