Browsing by Subject "Streptozotocin"

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    The FDA-approved anti-cancer drugs, streptozotocin and floxuridine, reduce the virulence of Staphylococcus aureus
    (Nature Publishing Group, 2018-02-06) Yeo, Won-Sik; Arya, Rekha; Kim, Kyeong Kyu; Jeong, Hyunyoung; Cho, Kyu Hong; Bae, Taeok; Microbiology and Immunology, School of Medicine
    In Staphylococcus aureus, an important Gram-positive human pathogen, the SaeRS two-component system is essential for the virulence and a good target for the development of anti-virulence drugs. In this study, we screened 12,200 small molecules for Sae inhibitors and identified two anti-cancer drugs, streptozotocin (STZ) and floxuridine (FU), as lead candidates for anti-virulence drug development against staphylococcal infections. As compared with STZ, FU was more efficient in repressing Sae-regulated promoters and protecting human neutrophils from S. aureus-mediated killing. FU inhibited S. aureus growth effectively whereas STZ did not. Intriguingly, RNA-seq analysis suggests that both compounds inhibit other virulence-regulatory systems such as Agr, ArlRS, and SarA more efficiently than they inhibit the Sae system. Both compounds induced prophages from S. aureus, indicating that they cause DNA damages. Surprisingly, a single administration of the drugs was sufficient to protect mice from staphylococcal intraperitoneal infection. Both compounds showed in vivo efficacy in a murine model of blood infection too. Finally, at the experimental dosage, neither compound showed any noticeable side effects on blood glucose level or blood cell counts. Based on these results, we concluded that STZ and FU are promising candidates for anti-virulence drug development against S. aureus infection.
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    The nature and mechanism of B-Cytotoxic action of diabetogenic nitrosoureas
    (1977) Akpan, Jones Okon
    This investigation was initiated to test the hypothesis that streptozotocin (STZ) and N-methylnitrosourea (MNU) damage B-cells of islet of Langerhans by depleting islets pyridine nucleotide content. Islets of Langerhans isolated by the collagenase method from nonnal rats were exposed to STZ rmder various experimental conditions and islets pyridine nucleotide content was temporally correlated with cytotoxicity. Metabolic and insulin secretory function of islets of Langerhans were used as indices of B-cell toxicity. The nitrosoureas (STZ and MNU) exerted time-, dose-, and temperature-dependent suppression of glucose-stimulated insulin secretion. Identical studies indicated that rmlike the nitrosoureas, alloxan was B-cytotoxic at 0°c even in the presence of 16.7 mM glucose. Whereas 2 mM alloxan elicited transient but consistent release of insulin by islets perifused in low glucose (1.7 mM) at 37°c, there was no release of insulin by islets perifused with 5 mM STZ, The effect of 5 mM STZ or of 10 mM MNU can be completely inhibited by the simultaneous presence of nicotinamide, isonicotinamide, picolinamide and other primary amides (e.g. pyrazinamide and benzamide) at concentration of 20 mM. Glucose (16.7 mM), pyridine nucleotides (10 mM) and acid derivative of amides (e.g. nicotinic acid; 20 mM) were ineffective. 2-Deoxyglucose (20 mM) or 3-0-methylglucose (20 mM) offered partial protection. After exposure of islets to STZ (5 mM) or MNU (10 mM), complete reversal of the effect was obtained with nicotinamide (20 mM) or its isomers, with time of exposure not exceeding 30 minutes. Beyond 30 minutes, the reversibility was partial or absent, except in the presence of 0.5 mM phenazine methosulfate (PMS) which induced release of insulin in both normal and nitrosoureas pre-treated islets. Insulin releasing action of PMS was dose-, time- and temperature-related; occurred even in the absence of glucose; was inhihitcd hy epinephrine (10 mM, hut not by mannoheptulose (20 mM); and was not potentiatcd by cyclic AMP (5 mM) or theophylline (10 mM). In the perifusion system, the patterns of response induced by PMS (0,5 mM) was spike-like release reaching a maximum in 5 minutes and declining rapidly to half-maximal value in 10 minutes. Normal islets pre-exposed to PMS was refractory to subsequent glucose (16.7 mM) stimulation. Islets pre-treated with STZ (1-5 mM) metaholized less 14c-glucose than control islets. The order of inhibition hy STZ of 14c-glucose metabolism by islet was: l-14C->U- 14C->6-14C-glucose. PMS (0.5 mM) augmented the metabolism of U-14C- and 1-14C glucose by STZ pre-treated islets. However, the metabolism of 6-14C-glucose was unelevated by PMS. The level of NADP+ + NADPII but not the level of NAD, decreased after two minutes exposure of islets to STZ. At thirty minutes, however, the levels of NAD,6-phosphogluconate and NADP+ + NADPII were decreased. The depletion paralleled suppression of insulin secretion. The level of NADP+ + NADPH in islets was decreased more than the level of NAD. Whereas PMS (0.5 mM) elevated the level of NADP+ + NADPH, the level of NAD was not augmented. Islets isolated from rats 3 or more hours after pre-injection with STZ (65 mg/kg) or 6-aminonicotinamide (40 mg/kg) failed to secrete insulin in response to glucose stimulation. However, insulin secretion by such islets was elevated in the presence of PMS (0.5 mM). Whereas PMS induced insulin secretion was much reduced 48 hours after preinjection of rats with STZ, the secretory activity in islets of rats 48 hours after 6-aminonicotinamide injection was slightly decreased. Pyridine nucleotides augmented secretion only in islets of 6-aminonicotinamide pre-injected rats. It is concluded that the immediate response of islets to nitrosoureas in vitro differs from islets response to alloxan. The actions of STZ and MNU are qualitatively similar. The B-cytotoxic effect of nitrosoureas is exerted directly or indirectly on the metabolic and energy coupling functions of pyridine coenzymes. Such an effect could be reversed by supplying the islets with reactive proton donors as substitutes for pyridine nucleotides.
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    Sex-Specific Bone Phenotype in the Streptozotocin-Induced Murine Model of Diabetes
    (2021-08) Hatch, Jennifer; Wallace, Joseph M.; Allen, Matthew R.; Bone, Robert N.; Li, Jilliang; Na, Sungsoo
    Bone disease and degradation is a ubiquitous problem, the complexity and treatment of which humanity has only begun to understand. Diabetes Mellitus is a disease which, in all forms, profoundly effects the organs of the body, bone included. As is often the case in biology, there are inherent differences between the sexes when considering skeletal development and disease progression and outcome. Although there are several reported mouse models for diabetes, until now there has been no characterization of bone disease in any model where diabetes occurs with equal frequency in males and females in greater than 90% of animals. In this study, a protocol for reliable induction of diabetes in both sexes using intraperitoneal injections of Streptozotocin was developed. The resulting bone phenotype in male and female mice was characterized and compared to weight and age matched control groups. In this model female diabetic mice exhibited a robust deficit in bone quality, while both sexes experienced loss of beta-cell mass and increased glycation of hemoglobin rendering the diabetic mice unable to produce insulin endogenously. Further, these mice were unable to metabolize exogenous insulin injected during insulin tolerance testing. This model is a strong candidate for future exploration of osteoporotic bone disease, Diabetes Mellitus, and the link between estrogen and glucose sensitivity.
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    Stress-inducible Mig6 promotes pancreatic beta cell destruction in the pathogenesis of diabetes
    (2014-12-08) Chen, Yi-Chun; Fueger, Patrick T.; Day, Richard N.; Elmendorf, Jeffrey S.
    Pancreatic insulin-secreting beta cell failure is central to the development of diabetes. Therapeutic applications targeted at understanding and manipulating beta cell destruction mechanisms should enhance the preservation of functional beta cell mass and prevent diabetes. To this end, we have demonstrated that diabetogenic assaults (e.g., endoplasmic reticulum stress, glucolipotoxicity, and pro-inflammatory cytokines) attenuate the activation of beta cell pro-survival signaling pathways via a stress-inducible molecule called Mitogen-inducible gene 6 (Mig6). We discovered that the overabundance of Mig6 exacerbates stress-induced beta cell apoptosis and inhibits insulin secretion. Conversely, the deficiency of Mig6 partially protected beta cells from DNA damage-induced cell death. Further, we established that Mig6 haploinsufficient mice retained islet integrity and function and exhibited greater beta cell mass recovery following treatment with multiple low doses of the beta cell toxin streptozotocin. These data suggest that Mig6 may be a therapeutic target for beta cell preservation in diabetes.