Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P42574 (caspase-3)
 45,978 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Increasing evidences in both experimental and clinical studies suggest that oxidative stress is involved in the pathogenesis of diabetic tissue damage. Pancreatic beta-cell death is the cause of decreased insulin production in diabetes. Streptozotocin (STZ) is widely used to induce experimental diabetes due to its ability to selectively target and destroy insulin producing pancreatic beta-cells via the formation of both reactive oxygen species (ROS) and RNS (reactive nitrogen species). This study investigated the prophylactic role of arjunolic acid (AA) against STZ-induced diabetes in the pancreas tissue of the Swiss albino rats (as a working model). We observed that STZ administration (at a dose of 65mg/kg body weight, injected in the tail vain) caused increased production of both ROS and RNS in the pancreas tissue of experimental animals. Formation of these reactive intermediates decreased the intracellular antioxidant defense, increased the levels of lipid peroxidation, protein carbonylation, serum glucose and TNF-alpha. Investigating the signaling pathways, we found that STZ administration caused the activation of phospho-ERK1/2, phospho-p38, NF-kappaB and destruction of mitochondrial transmembrane potential, release of cytochrome c as well as activation of caspase 3 in the pancreas tissue keeping the levels of total ERK1/2 and p38 significantly unchanged. Treatment of animals with AA (at a dose of 20mg/kg body weight, orally) both prior and post to the STZ administration effectively reduced these adverse effects by inhibiting the excessive ROS and RNS formation as well as by down-regulating the activation of phospho-ERK1/2, phospho-p38, NF-kappaB and mitochondrial dependent signal transduction pathways leading to apoptotic cell death. Combining all, these results suggest that AA plays some beneficial roles against STZ-induced diabetes.
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PMID:Protective role of arjunolic acid in response to streptozotocin-induced type-I diabetes via the mitochondrial dependent and independent pathways. 1913 11

Cyanide is a rapidly acting mitochondrial poison that inhibits cellular respiration and energy metabolism leading to histotoxic hypoxia followed by cell death. Cyanide is predominantly a neurotoxin but its toxic manifestations in non-neuronal cells are also documented. This study addresses the oxidative stress mediated cytotoxicity of cyanide in Rhesus monkey kidney epithelial cells (LLC-MK2). Cells were treated with various concentrations of potassium cyanide (KCN) for different time intervals and cytotoxicity was evidenced by increased leakage of intracellular lactate dehydrogenase, mitochondrial dysfunction (MTT assay) and depleted energy status of cells (ATP assay). Cytotoxicity was accompanied by lipid peroxidation indicated by elevated levels of malondialdehyde (MDA), reactive oxygen species (ROS) and reactive nitrogen species (RNS) (DCF-DA staining), diminished cellular antioxidant status (reduced glutathione (GSH), glutathione peroxidase, superoxide dismutase and catalase). These cascading events triggered an apoptotic kind of cell death characterized by oligonucleosomal DNA fragmentation and nuclear fragmentation (Hoechst 33342 staining). Apoptosis was further confirmed by increased caspase-3 activity. Cyanide-induced cytotoxicity, oxidative stress, and DNA fragmentation were prevented by alpha-ketoglutarate (A-KG) and N-acetyl cysteine (NAC). A-KG is a potential cyanide antidote that confers protection by interacting with cyanide to form cyanohydrin complex while NAC is a free radical scavenger and enhances the cellular GSH levels. The study reveals cytotoxicity of cyanide in cells of renal origin and the protective efficacy of A-KG and NAC.
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PMID:Oxidative stress mediated cytotoxicity of cyanide in LLC-MK2 cells and its attenuation by alpha-ketoglutarate and N-acetyl cysteine. 1913 48

Programmed cell death is necessary for homeostasis in multicellular organisms and it is also widely recognized to occur in unicellular organisms. However, the mechanisms through which it occurs in unicells, and the enzymes involved within the final response is still the subject of heated debate. It is shown here that exposure of the unicellular microalga Dunaliella viridis to several environmental stresses, induced different cell death morphotypes, depending on the stimulus received. Senescent cells demonstrated classical and unambiguous apoptotic-like characteristics such as chromatin condensation, DNA fragmentation, intact organelles, and blebbing of the cell membrane. Acute heat shock caused general swelling and altered plasma membrane, but the presence of chromatin clusters and DNA strand breaks suggested a necrotic-like event. UV irradiated cells presented changes typical for necrosis, together with apoptotic characteristics resembling an intermediate cell-death phenotype termed aponecrosis-like. Cells subjected to hyperosmotic shock revealed chromatin spotting without DNA fragmentation, and extensive cytoplasmic swelling and vacuolization, comparable to a paraptotic-like cell death phenotype. Nitrogen-starved cells showed pyknosis, blebbing, and cytoplasmic consumption, indicating a similarity to autophagic/vacuolar-like cell death. The caspase-like activity DEVDase was measured by using the fluorescent substrate Ac-DEVD-AMC and antibodies against the human caspase-3 active enzyme cross-reacted with bands, the intensity of which paralleled the activity. All the environmental stresses tested produced a substantial increase in both DEVDase activity and protein levels. The irreversible caspase-3 inhibitor Z-DEVD-FMK completely inhibited the enzymatic activity whereas serine and aspartyl proteases inhibitors did not. These results show that cell death in D. viridis does not conform to a single pattern and that environmental stimuli may produce different types of cell death depending on the type and intensity of the stimulus, all of which help to understand the cell death-dependent and cell death-independent functions of caspase-like proteins. Hence, these data support the theory that alternative, non-apoptotic programmed cell death (PCDs), exist either in parallel or in an independent manner with apoptosis and were already present in single-celled organisms that evolved some 1.2-1.6 billion years ago.
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PMID:Different ways to die: cell death modes of the unicellular chlorophyte Dunaliella viridis exposed to various environmental stresses are mediated by the caspase-like activity DEVDase. 1925 86

Prolonged ischemia amplified iscehemia/reperfusion (IR) induced renal apoptosis and autophagy. We hypothesize that ischemic conditioning (IC) by a briefly intermittent reperfusion during a prolonged ischemic phase may ameliorate IR induced renal dysfunction. We evaluated the antioxidant/oxidant mechanism, autophagy and apoptosis in the uninephrectomized Wistar rats subjected to sham control, 4 stages of 15-min IC (I15 x 4), 2 stages of 30-min IC (I30 x 2), and total 60-min ischema (I60) in the kidney followed by 4 or 24 hours of reperfusion. By use of ATP assay, monitoring O2-. amounts, autophagy and apoptosis analysis of rat kidneys, I60 followed by 4 hours of reperfusion decreased renal ATP and enhanced reactive oxygen species (ROS) level and proapoptotic and autophagic mechanisms, including enhanced Bax/Bcl-2 ratio, cytochrome C release, active caspase 3, poly-(ADP-ribose)-polymerase (PARP) degradation fragments, microtubule-associated protein light chain 3 (LC3) and Beclin-1 expression and subsequently tubular apoptosis and autophagy associated with elevated blood urea nitrogen and creatinine level. I30 x 2, not I15 x 4 decreased ROS production and cytochrome C release, increased Manganese superoxide dismutase (MnSOD), Copper-Zn superoxide dismutase (CuZnSOD) and catalase expression and provided a more efficient protection than I60 against IR induced tubular apoptosis and autophagy and blood urea nitrogen and creatinine level. We conclude that 60-min renal ischemia enhanced renal tubular oxidative stress, proapoptosis and autophagy in the rat kidneys. Two stages of 30-min ischemia with 3-min reperfusion significantly preserved renal ATP content, increased antioxidant defense mechanisms and decreased ischemia/reperfusion enhanced renal tubular oxidative stress, cytosolic cytochrome C release, proapoptosis and autophagy in rat kidneys.
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PMID:Ischemic conditioning by short periods of reperfusion attenuates renal ischemia/reperfusion induced apoptosis and autophagy in the rat. 1927 87

Sildenafil was the first selective inhibitor of phosphodiesterase-5 (PDE5) to be widely used for treating erectile dysfunction. Many recent studies have investigated the cardioprotective role of sildenafil in animal models. We evaluated the protective effects of sildenafil in experimental renal ischemia-reperfusion (IR) injury in two studies. In study 1, male Sprague-Dawley rats were divided into four groups: sham, sildenafil-treated sham, vehicle-treated IR, and sildenafil-treated IR groups. In study 2, we divided the rats into two groups: sildenafil-treated IR rats and PD98059 (ERK inhibitor)+sildenafil-treated IR rats. Functional parameters of the kidney were evaluated at the molecular and structural levels. Blood urea nitrogen (BUN) and serum creatinine levels were lower in sildenafil-treated IR rats than in vehicle-treated IR rats. The expression of inducible (iNOS) and endothelial nitric oxide synthase (eNOS) proteins in sildenafil-treated IR rats was significantly higher than in vehicle-treated IR rats. Pretreatment with sildenafil in IR rats increased ERK phosphorylation and reduced the renal Bax/Bcl-2 ratio, renal caspase-3 activity, and terminal dUTP nick end-labeling-positive apoptotic cells. In contrast, PD98059 treatment increased BUN and serum creatinine levels and attenuated the sildenafil-induced expression of pERK, iNOS, eNOS, and Bcl-2. PD98059 also increased caspase-3 activity but did not decrease the sildenafil-induced accumulation of cGMP. In conclusion, this study suggests that sildenafil has antiapoptotic effects in experimental IR renal injury via ERK phosphorylation, induction of iNOS and eNOS production, and a decrease in the Bax/Bcl-2 ratio.
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PMID:Pretreatment of sildenafil attenuates ischemia-reperfusion renal injury in rats. 1947 86

X-radiation (10cGy) was shown to induce in human lymphocytes transposition of homologous chromosomes loci from the membrane towards the centre of the nucleus and activation of the chromosomal nucleolus-forming regions (NFRs). These effects are transmitted by means of extracellular DNA (ecDNA) fragments to nonirradiated cells (the so-called bystander effect, BE). We demonstrated that in the development of the BE an important role is played by oxidative stress (which is brought about by low radiation doses and ecDNA fragments of the culture medium of the irradiated cells), by an enzyme of apoptosis called caspase-3, and by DNA-binding receptors of the bystander cells, presumably TLR9. Proposed herein is a scheme of the development of an adaptive response and the BE on exposure to radiation. Ionizing radiation induces apoptosis of the radiosensitive fraction of cells due to the development of the "primary" oxidative stress (OS). DNA fragments of apoptotic cells are released into the intercellular space and interact with the DNA-binding receptors of the bystander cells. This interaction activates in lymphocytes signalling pathways associated with synthesis of the reactive oxygen species and nitrogen species, i.e., induces secondary oxidative stress accompanied by apoptosis of part of the cells, etc. Hence, single exposure to radiation may be followed by relatively long-lasting in the cellular population oxidative stress contributing to the development of an adaptive response. We thus believe that ecDNA of irradiated apoptotic lymphocytes is a significant factor of stress-signalling.
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PMID:Oxidative stress as a significant factor for development of an adaptive response in irradiated and nonirradiated human lymphocytes after inducing the bystander effect by low-dose X-radiation. 1954 Feb 46

Free radicals are involved in pathophysiology of ischemia/reperfusion injury (IRI). Melatonin is a potent scavenger of reactive oxygen and nitrogen species. Thus, this study was designed to elucidate its effects in a model of rat kidney transplantation. Twenty Lewis rats were randomly divided into 2 groups (n = 10 animals each). Melatonin (50 mg/kg BW) dissolved in 5 mL milk was given to one group via gavage 2 hr before left donor nephrectomy. Controls were given the same volume of milk only. Kidney grafts were then transplanted into bilaterally nephrectomized syngeneic recipients after 24 hr of cold storage in Histidine-Tryptophan-Ketoglutarate solution. Both graft function and injury were assessed after transplantation through serum levels of blood urea nitrogen (BUN), creatinine, transaminases, and lactate dehydrogenase (LDH). Biopsies were taken to evaluate tubular damage, the enzymatic activity of superoxide dismutase (SOD) and lipid hydroperoxide (LPO), and the expression of NF-kBp65, inducible nitric oxide synthase (iNOS), caspase-3 as indices of oxidative stress, necrosis, and apoptosis, respectively. Melatonin improved survival (P < 0.01) while decreasing BUN, creatinine, transaminases, and LDH values up to 39-71% (P < 0.05). Melatonin significantly reduced the histological index for tubular damage, induced tissue enzymatic activity of SOD while reducing LPO. At the same time, melatonin down-regulated the expression of NF-kBp65, iNOS, and caspase-3. In conclusion, donor preconditioning with melatonin protected kidney donor grafts from IRI-induced renal dysfunction and tubular injury most likely through its anti-oxidative, anti-apoptotic and NF-kB inhibitory capacity.
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PMID:Melatonin protects kidney grafts from ischemia/reperfusion injury through inhibition of NF-kB and apoptosis after experimental kidney transplantation. 1955 59

Diabetic neuropathic pain, an important microvascular complication in diabetes mellitus, is recognised as one of the most difficult types of pain to treat. The development of tolerance, inadequate relief and potential toxicity of classical antinociceptives warrant the investigation of the newer agents to relieve this pain. Reactive oxygen/nitrogen species, cytokines and apoptosis are implicated in the pathogenesis of diabetic neuropathy. The aim of the present study was to explore the effect of tocotrienol on thermal and mechanical hyperalgesia, allodynia, oxidative-nitrosative stress, inflammation and apoptosis in streptozotocin-induced experimental diabetes. Diabetic rats developed neuropathy which was evident from a marked hyperalgesia and allodynia associated with enhanced nitrosative stress, release of inflammatory mediators (TNF-alpha, IL-1beta, TGF-1beta) and caspase-3. Chronic treatment with tocotrienol (25, 50 and 100 mg/kg body weight; p.o.) for 4 weeks starting from the 4th week of streptozotocin injection significantly attenuated behavioral, biochemical and molecular changes associated with diabetic neuropathy. Moreover, diabetic rats treated with insulin-tocotrienol combination produced more pronounced beneficial effect as compared to their per se groups. The major finding of the study is that insulin alone corrected the hyperglycemia and partially reversed the pain response in diabetic rats. However, combination with tocotrienol not only attenuated the diabetic condition but also reversed neuropathic pain through modulation of oxidative-nitrosative stress, inflammatory cytokine release and caspase-3 in the diabetic rats and thus it may find clinical application to treat neuropathic pain in the diabetic patients.
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PMID:Tocotrienol attenuates oxidative-nitrosative stress and inflammatory cascade in experimental model of diabetic neuropathy. 1955 1

In this report, we describe the synthesis and characterization of nanocrystalline silicalite (the purely siliceous form of the zeolite, ZSM-5) of defined crystal size and surface functionalization and determine the effect on the type and degree of cytotoxicity induced in two distinct model cell lines. The silicalite materials were characterized by powder X-ray diffraction, dynamic light scattering and zeta potential, solid state NMR, thermal gravimetric analysis, and nitrogen adsorption using the BET method to determine specific surface area. The silicalite samples were functionalized with amino, thiol, and carboxy groups and had crystal sizes of approximately 30, 150, and 500 nm. The cytotoxicities of the silicalite samples with different crystal sizes and different surface functional groups were investigated using human embryonic kidney 293 (HEK-293) cells and RAW264.7 macrophage cell lines. We used the lactic dehydrogenase release assay to measure damage to the cell membrane, the caspase 3/7 activity assay to measure key molecules involved in apoptosis, and the Annexin V-propidium iodide staining method to provide visual confirmation of the types of cell death induced. We have shown that the impact of size and surface functionalization of silicalite nanoparticles on cell toxicity and mechanism of cell death is cell type-dependent. Thirty nanometer silicalite nanoparticles were nontoxic in RAW264.7 cells relative to untreated controls but caused necrosis in HEK293 cells. Carboxy-functionalized 500 nm silicalite nanoparticles resulted in apoptosis and necrosis in RAW264.7 cells and predominantly activated apoptosis in HEK293 cells.
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PMID:Effect of crystal size and surface functionalization on the cytotoxicity of silicalite-1 nanoparticles. 1958 Mar 8

Diabetes has become the most common single cause of end-stage renal disease (ESRD) in the United States and Europe. Approximately 30-40% of patients with type I and 15% with type II diabetes mellitus develop end ESRD. The study was designed to evaluate the impact of sesamol on renal function and renoinflammatory cascade in streptozotocin (STZ)-induced diabetes. STZ-induced diabetic rats were treated with sesamol (2, 4, and 8 mg/kg/day; po) or with vehicle from the fifth to eighth weeks. After 8 weeks, urine albumin excretion, urine output, serum creatinine, blood urea nitrogen, creatinine, and urea clearance were measured. Cytoplasmic and nuclear fractions of kidney were prepared for the quantification of oxidative-nitrosative stress (lipid peroxidation, superoxide dismutase, catalase, nonprotein thiols, total nitric oxide), tumor necrosis factor-alpha (TNF-alpha), tissue growth factor-1 beta (TGF-beta1), p65 subunit of NFkappabeta, and caspase-3. After 8 weeks of STZ injection, the rats produced significant alteration in renal function, increased oxidative-nitrosative stress, TNF-alpha, TGF-beta1, caspase-3 activity in cytoplasmic lysate, and active p65 subunit of NFkappabeta in nuclear lysate of kidney of diabetic rats. Interestingly, co-administration of sesamol significantly and dose-dependently prevented biochemical and molecular changes associated with diabetes. Moreover, diabetic rats treated with insulin-sesamol combination produced more pronounced effect on molecular parameters as compared to their respective groups. The data reveal that sesamol modulates the release of profibrotic cytokines, oxidative stress, ongoing chronic inflammation, and apoptosis and thus exerts a marked renoprotective effect.
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PMID:Attenuation of renoinflammatory cascade in experimental model of diabetic nephropathy by sesamol. 1960 60


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