Metabolic effects of sleeve gastrectomy in female rat model of diet-induced obesity

BackgroundAlthough women disproportionately undergo bariatric surgery, the rodent models investigating the mechanisms of bariatric surgery have been limited to males. Female rodent models can also potentially allow us to understand the effects of surgical intervention on future generations of offspring. Sleeve gastrectomy is an attractive weight loss procedure for reproductive-age female patients because it avoids the malabsorption associated with intestinal bypass. We sought to evaluate the effect of sleeve gastrectomy on young female rats with diet-induced obesity at the University of California, Los Angeles, David Geffen School of Medicine.MethodsSprague-Dawley female rats were fed a 60% high-fat diet. At 12 weeks of age, the rats underwent either sleeve gastrectomy or sham surgery. The rats were killed 4 weeks after surgery. A chemistry panel was performed, and the serum adipokines and gut hormones were assayed. The homeostasis model assessment score was calculated. The liver histologic findings were graded for steatosis. The 2-sample t test was used to compare the results between the 2 groups.ResultsSleeve gastrectomy was associated with significant weight loss (5% ± 6% versus ?4% ± 6%; P < .001), lower leptin levels (1.3 ± 1.2 versus 3.5 ± 2.3 ng/mL; P < .01), and higher adiponectin levels (.43 ± .19 versus .17 ± .14 ng/mL; P < .004) compared with the sham-operated rats. No significant differences were found in the fasting ghrelin levels. Furthermore, we did not observe evidence of insulin resistance or steatohepatitis after 11 weeks of high-fat diet. Despite these limitations, additional gender-specific studies are warranted given that most bariatric surgeries are performed in women.ConclusionSleeve gastrectomy appears to result in weight loss and improvements in adiponectin and leptin by way of mechanisms independent of ghrelin levels in a female model of diet-induced obesity.     

Cancer resistance in transgenic mice expressing the SAC module of Par-4

Prostate apoptosis response-4 (Par-4) is a tumor-suppressor protein that induces apoptosis in cancer cells, but not in normal/immortalized cells. The cancer-specific proapoptotic action of Par-4 is encoded in its centrally located SAC domain. We report here the characterization of a novel mouse model with ubiquitous expression of the SAC domain. Although SAC transgenic mice displayed normal development and life span, they were resistant to the growth of spontaneous, as well as oncogene-induced, autochthonous tumors. Resistance to tumorigenesis was linked to inhibition of nuclear factor-kappaB activity and induction of apoptosis by the SAC domain. Collectively, our findings provide genetic evidence that the SAC domain of Par-4 confers cancer resistance in transgenic mice without compromising normal viability or aging, and may have therapeutic significance.     

Lipid abnormalities in streptozotocin-diabetes: Amelioration by Morus indica L. cv Suguna leaves

AIM:

To observe the influence of mulberry (Morus indica L. cv Suguna) leaves on lipid abnormalities in STZ-diabetic rats.

MATERIALS AND METHODS:

Treatment with dried mulberry leaf powder for a period of 8 weeks in hyperglycemic and hyperlipidemic STZ-diabetic rats.

RESULTS:

Mulberry leaves regulated fasting blood glucose, ameliorated the abnormalities in lipid profile as indicated by significant (P<0.01) decrease in serum triglycerides, phospholipids, cholesterol and plasma free fatty acids by 50, 6, 31 and 22% respectively in STZ- diabetic rats compared to diabetic control rats which had significantly (P<0.01) raised levels of triglycerides, phospholipids, cholesterol and free fatty acids than the normal control rats. A marked increase in fecal bile acids (154%) was observed in mulberry treated diabetic rats compared to the diabetic control group indicating conversion of cholesterol to bile acids. In addition, mulberry supplementation significantly lowered LDL-C (67%) and VLDL-C (44%) levels and increased HDL-C (53%) and also decreased atherogenic index (58%) significantly when compared to the diabetic control group.

CONCLUSION:

Besides the diabetic rats, mulberry leaves affected lipid profile in normal rats also indicating hypolipidemic effect as a result of the synergistic action of bioactive compounds.     

Identification of Putative Cytoskeletal Protein Homologues in the Protozoan Host Hartmannella vermiformis as Substrates for Induced Tyrosine Phosphatase Activity upon Attachment to the Legionnaires' Disease Bacterium,Legionella pneumophila

The Legionnaires'' disease bacterium, Legionella pneumophila, is a facultative intracellular pathogen that invades and replicates within two evolutionarily distant hosts, free living protozoa and mammalian cells. Invasion and intracellular replication within protozoa are thought to be major factors in the transmission of Legionnaires'' disease. We have recently reported the identification of a galactose/N-acetyl-d-galactosamine (Gal/GalNAc) lectin in the protozoan host Hartmannella vermiformis as a receptor for attachment and invasion by L. pneumophila (Venkataraman, C., B.J. Haack, S. Bondada, and Y.A. Kwaik. 1997. J. Exp. Med. 186:537–547). In this report, we extended our studies to the effects of bacterial attachment and invasion on the cytoskeletal proteins of H. vermiformis. We first identified the presence of many protozoan cytoskeletal proteins that were putative homologues to their mammalian counterparts, including actin, pp125^FAK, paxillin, and vinculin, all of which were basally tyrosine phosphorylated in resting H. vermiformis. In addition to L. pneumophila–induced tyrosine dephosphorylation of the lectin, bacterial attachment and invasion was associated with tyrosine dephosphorylation of paxillin, pp125^FAK, and vinculin, whereas actin was minimally affected. Inhibition of bacterial attachment to H. vermiformis by Gal or GalNAc monomers blocked bacteria-induced tyrosine dephosphorylation of detergent-insoluble proteins. In contrast, inhibition of bacterial invasion but not attachment failed to block bacteria-induced tyrosine dephosphorylation of H. vermiformis proteins. This was further supported by the observation that 10 mutants of L. pneumophila that were defective in invasion of H. vermiformis were capable of inducing tyrosine dephosphorylation of H. vermiformis proteins. Entry of L. pneumophila into H. vermiformis was predominantly mediated by noncoated receptor-mediated endocytosis (93%) but coiling phagocytosis was infrequently observed (7%). We conclude that attachment but not invasion by L. pneumophila into H. vermiformis was sufficient and essential to induce protein tyrosine dephosphorylation in H. vermiformis. These manipulations of host cell processes were associated with, or followed by, entry of the bacteria by a noncoated receptor-mediated endocytosis. A model for attachment and entry of L. pneumophila into H. vermiformis is proposed.     

Differential regulation of surface immunoglobulin and Lyb2 mediated B cell activation: II. cAMP dependent (prostaglandin E2) and independent (IFN-{gamma}) mechanisms of regulation of B lymphocyte activation

We have recently demonstrated that pharmacological agents thatelevated cAMP inhibited sigM but not Lyb2 mediated activationof murine B lymphocytes. In this report we show evidence fordifferential regulation of prostagiandin E₂ (PGE₂), a physiologicalagent that elevated cAMP and IFN- on sigM and Lyb2 mediatedB cell activation. PGE₂ inhibited anti-lgM but not anti-Lyb2induced DNA synthesis in a dose-dependent manner. Interestingly,rlFN- also inhibited anti-lgM but not anti-Lyb2 induced DNAsynthesis. rlFN- exerted its effects directly on B cells sincedepletion of T cells and G-10 Sephadex adherent cells did notalter effects of IFN- on anti-lgM and anti-Lyb2 induced DNAsynthesis. Pretreatment of B cells with IL-4 and/or IL-5 didnotprevent the IFN- mediated inhibition of the anti-lgM response.The inhibitory effect of IFN- was observed during early stagesof B cell activation. Thus IFN- inhibited anti-µ inducedblast transformation and subsequent progression into the G₁phase of the cell cycle. The differential effects exerted byPGE₂ and rIFN- appeared to be mediated by distinct mechanisms.ThusPGE₂ but not rIFN-, at concentrations inhibitory to the slgMresponse, induced elevation of intracellular cAMP levels. Theseresults demonstrate that physiologically relevant immunomodulatorssuch as PGE₂ and IFN- can differentially regulate murine B cellresponses mediated through the antigen receptor and Lyb2 moleculesby cAMP dependent and independent mechanisms. Relevance of thisregulation for the induction of antibody synthesis by T_h1 andT_h2 types of helper T cells is discussed.     

Curcumin causes the growth arrest and apoptosis of B cell lymphoma by downregulation of egr-1, c-myc, bcl-XL, NF-kappa B, and p53.

It has been well known that curcumin is a powerful inhibitor of proliferation of several tumor cells. However, the molecular basis of the anti-proliferative effect of curcumin has not been investigated in detail. In this paper, we present evidence to show that curcumin inhibited proliferation of a variety of B lymphoma cells. At low concentrations curcumin inhibited the proliferation of BKS-2, an immature B cell lymphoma, more effectively than that of normal B lymphocytes and caused the apoptosis of BKS-2 cells in a dose- and time-dependent manner. Furthermore, curcumin downregulated the expression of survival genes egr-1, c-myc, and bcl-X(L) as well as the tumor suppressor gene p53 in B cells. In addition, NF-kappaB binding activity was also downregulated almost completely by curcumin. Stimulation with CpG oligonucleotides or anti-CD40 overcame growth inhibition induced by low concentrations of curcumin. Our results suggest that curcumin caused the growth arrest and apoptosis of BKS-2 immature B cell lymphoma by downregulation of growth and survival promoting genes.     

Bacterial lipopolysaccharide induced B cell activation is mediated via a phosphatidylinositol 3-kinase dependent signaling pathway.

Bacterial lipopolysaccharide (LPS) is a potent stimulant of B cells and macrophages. LPS induces B cell proliferation and differentiation into antibody secreting cells. In addition, LPS also stimulates IL-6 secretion in mature B cells and in immature B cell lines such as WEHI-231. Although sufficient literature is available on LPS induced signaling events in monocytes and macrophages, the mechanisms involved in LPS induced B cell activation are not well understood. In this report, it is shown that both LPS mediated B cell proliferation and IL-6 secretion are dependent on phosphatidylinositol 3-kinase (PI 3-kinase) signaling pathways. The B cell specific co-receptor, CD19 is not tyrosine phosphorylated in LPS stimulated B cells. Thus, in contrast to B cell antigen receptor (BCR) signaling, the activation of PI 3-kinase appears not to be related to the recruitment of PI 3-kinase to tyrosine phosphorylated CD19. This is the first demonstration of the importance of PI 3-kinase signaling pathway in LPS mediated B lymphocyte activation.     

Mitochondrial μ-calpain is not involved in the processing of apoptosis-inducing factor

Caspase-independent cell death, an important death pathway in many cells including neurons, is executed via apoptosis-inducing factor (AIF), an oxidoreductase, localized to the mitochondrial intermembrane space. AIF is processed and released from mitochondria following mitochondrial permeability transition pore (mPTP) formation, and translocates to the nucleus to induce DNA fragmentation and cell death. The release of AIF requires cleavage of its N-terminus anchored in the inner mitochondrial membrane. The protease responsible for this AIF truncation has not been established, although there is considerable evidence suggesting a role for μ-calpain. We previously found that a pool of μ-calpain is localized to the mitochondrial intermembrane space, the submitochondrial compartment in which AIF truncation occurs. The close submitochondrial proximity of mitochondrial μ-calpain and AIF gives support to the hypothesis that mitochondrial μ-calpain may be the protease responsible for processing AIF prior to its release. In the present study, AIF was released from rat liver mitochondria following mPTP induction by atractyloside. This release was inhibited by the cysteine protease inhibitor MDL28170, but not by more specific calpain inhibitors PD150606 and calpastatin. Atractyloside caused swelling in rat brain mitochondria, but did not induce AIF release. In a mitochondrial fraction from SH-SY5Y neuroblastoma cells, incubation with 5 mM Ca²⁺ resulted in the activation of μ-calpain but not in AIF truncation. In summary, the localization of μ-calpain to the mitochondrial intermembrane space is suggestive of its possible involvement in AIF processing, but direct experimental evidence supporting such a role has been elusive.