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Items 2901 to 2905 of 2909 total

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  • Acute and delayed renal protection against renal ischemia and reperfusion injury with A1 adenosine receptors

    Joo, J; Kim, M; Horst, P; Kim, J; D'Agati, V; Emala, C; Lee, H;
    Department of 1 Anesthesiology and 2 Pathology, College of Physicians and Surgeons of Columbia University, New York, NY, 10032, U.S.A
    We showed previously that activation of A1 adenosine receptors (AR) protects against renal ischemia-reperfusion (IR) injury in rats and mice. In the heart, transient A1AR activation produces biphasic protective effects: acute protection wanes after several hours but protective effects return 24–72 h later (second window of protection). In this study, we determined whether A1AR activation produces delayed renal protection and elucidated the mechanisms of acute and delayed renal protection. A1AR wild-type mice were subjected to 30-min renal ischemia and 24 h of reperfusion to produce acute renal failure. Pretreatment with a selective A1AR agonist 2-chloro-N6-cyclopentyladenosine (CCPA; 0.1 mg/kg bolus ip) either 15 min or 24 h before renal ischemia protected against renal IR injury and reduced renal corticomedullary necrosis, apoptosis, and inflammation. Transient A1AR activation led to phosphorylation of extracellular signal-regulated protein kinase mitogen-activated protein kinase (ERK MAPK), Akt, and heat shock protein 27 (HSP27). Moreover, induction of HSP27 and Akt occurred with CCPA treatment. Inhibition of PKC with chelerythrine prevented acute but not delayed renal protection with A1AR activation. Moreover, deletion of PI3Kγ or inhibition of Akt, but not inhibition of ERK, prevented delayed and acute renal protection with A1AR activation. Inhibition of Gi/o with pertussis toxin obliterated both acute and delayed A1AR-mediated renal protection. In contrast to renal protection with delayed ischemic preconditioning, nitric oxide synthase activity was not induced with delayed A1AR-mediated renal protection. Therefore, transient activation of renal A1AR led to acute as well as delayed protective effects against renal IR injury via distinct signaling pathways.
    10.1152/ajprenal.00336.2007
  • Specific and prolonged proteasome inhibition dictates apoptosis induction by marizomib and its analogs

    Miller, CP; Manton, CA; Hale, R; Debose, L; Macherla, VR; Potts, BC; Palladino, MA; Chandra, J;
    Department of Pediatrics Research, Children's Cancer Hospital at M.D. Anderson, University of Texas M.D. Anderson Cancer Center, Houston, United States
    Product(s): Z-Leu-Leu-Glu-AMC
    Marizomib (NPI-0052) is a naturally derived irreversible proteasome inhibitor that potently induces apoptosis via a caspase-8 and ROS-dependent mechanism in leukemia cells. We aim to understand the relationship between the irreversible inhibition of the proteasome and induction of cell death in leukemia cells by using analogs of marizomib that display reversible and irreversible properties. We highlight the importance of sustained inhibition of at least two proteasome activities as being key permissive events for the induction of the apoptotic process in leukemia cells. These data provide the basis for the development of new approaches to generate more effective anti-proteasome therapies. Published by Elsevier Ireland Ltd.
    10.1016/j.cbi.2011.08.005
  • Limited activation of the intrinsic apoptotic pathway plays a main role in amyloid-β-induced apoptosis without eliciting the activation of the extrinsic apoptotic pathway

    Islam, MI; Sharoar, MG; Ryu, EK; Park, IS;
    Department of Medical Sciences, Chosun University, Gwangju 501-759, Republic of Korea
    Amyloid-β (Aβ), a main pathogenic factor of Alzheimer's disease (AD), induces apoptosis accompanied by caspase activation. However, limited caspase activation and the suppression of the intrinsic apoptotic pathway (IAPW) are frequently observed upon Aβ treatment. In this study, we investigated whether these suppressive effects of Aβ can be overcome; we also examined the death-related pathways. Single treatments of cells with Aβ42 for up to 48 h barely induced caspase activation. In cells treated with Aβ42 twice for 2 h followed by 22 h (2+22 h) or for longer durations, the apoptotic protease activating factor-1 (Apaf-1) apoptosome was formed and caspases-3 and -9 were activated to a certain extent, suggesting the activation of the IAPW. However, the Aβ42-induced activation of the IAPW differed from that induced by treatment with other agents, such as staurosporine (STS) in that lower amounts of cytochrome c were released from the mitochondria, the majority of procaspase-9 in the Apaf-1 complex was not processed and caspase-3 was activated to a lesser extent in the peptide-treated cells. Thus, it seemed that the IAPW was not fully activated by Aβ42. The 30- and 41/43-kDa fragments derived from procaspase-8 were detected, which appear to be produced through the IAPW without death-inducing signaling-complex (DISC) formation, a key feature of the extrinsic apoptotic pathway (EAPW). Bid cleavage was observed only after caspase-3 activity reached its maximal levels, suggesting that the cleavage may contribute in a limited capacity to the amplification process of the IAPW in the Aβ-treated cells. Taken together, our data suggest that the IAPW, albeit functional only to a limited extent, plays a major role in Aβ42-induced apoptosis without the EAPW.
    10.3892/ijmm.2017.3193
  • S‐Nitrosylation in Parkinson's Disease and Related Neurodegenerative Disorders

    Chung, K; Dawson, V; Dawson, T;
    Parkinson's disease (PD) is a common neurodegenerative disorder characterized by impairment in motor function. PD is mostly sporadic, but rare familial cases are also found. The exact pathogenic mechanism is not fully understood, but both genetic and environmental factors are known to be important contributors. In particular, oxidative stress mediated through nitric oxide (NO) is believed to be a prime suspect in the development of PD. NO can exert its effect by modifying different biological molecules, and one of these modifications is through _S_‐nitrosylation. Because of the liable nature of _S_‐nitrosylation, a number of methods are often used to study this modification. We have successfully employed some of these methods and showed that a familial related protein, parkin, can be _S_‐nitrosylated and provide a common pathogenic mechanism for sporadic and familial PD.
    10.1016/S0076-6879(05)96014-X
  • Caspase inhibitors block zinc-chelator induced death of retinal ganglion cells

    Shindler, KS; Zurakowski, D; Dreyer, EB;
    Department of Ophthalmology, University of Pennsylvania, Veteran's Administration, Scheie Eye Institute, Philadelphia 19104, USA
    Zinc-chelating agents, including ethambutol and its metabolite 2,2'(ethylenediamino)-dibutyric acid (EDBA) are toxic to retinal ganglion cells through a glutamate dependent mechanism. We explored whether such cell death was mediated through the caspase family of cysteine proteases. Retinal cultures were treated with EDBA alone, or EDBA plus a variety of known caspase inhibitors, and ganglion cell viability was assayed. EDBA killed 20-30% of ganglion cells. A general caspase inhibitor, BAF, prevented EDBA induced ganglion cell death. Specific inhibitors of caspase-3 and caspase-6 showed a similar ability to BAF in preventing EDBA mediated ganglion cell loss, whereas inhibitors of caspase-8 and caspase-9 were not able to rescue EDBA treated ganglion cells. A caspase-1,4 inhibitor was less effective than BAF. These studies show that a caspase mediated mechanism of apoptosis accents for a portion of EDBA mediated retinal ganglion cell death. This toxicity was mediated by downstream effector caspases, 3 and 6. Caspase inhibitors may prevent ganglion cell death secondary to ethambutol treatment.

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