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At least 127 records · Page 7Linked to original sources
PubMed2003

Lipid oxidative markers are significantly increased in lipoatrophy but not in sustained asymptomatic hyperlactatemia.

The exact mechanism of lipoatrophy remains unclear. One hypothesized mechanism is accumulation of reactive oxygen free radicals, which is possibly related to dysfunctional mitochondria. We evaluated plasma levels of F2-isoprostanes-the most accurate method to measure oxidant stress in vivo-in a group of 59 nucleoside reverse transcriptase inhibitor-treated HIV-1-infected subjects. All had serial measurements of venous lactate levels as well as clinical evaluations for assessment of lipoatrophy and symptoms of mitochondrial toxicity. Overall, 16 subjects had sustained hyperlactatemia (4 of whom were symptomatic) and 43 had serial normal lactate levels. We found a significant increase in circulating products of lipid peroxidation, F2-isoprostanes (nanograms per milliliter), in subjects with lipoatrophy when compared with subjects without lipoatrophy (0.060 +/- 0.025 vs. 0.0420 +/- 0.02, respectively; P = 0.02). Interestingly, there was no significant difference in F2-isoprostane levels (nanograms per milliliter) between patients with persistently normal lactate and those who exhibited a sustained asymptomatic hyperlactatemia (0.053 +/- 0.027 vs. 0.053 +/- 0.021, respectively; P > 0.05). This could be explained by the yet unclear significance of asymptomatic hyperlactatemia, even in a setting like ours, where lactate levels were measured with close attention to the method of collection and processing. In contrast, the 4 subjects with symptomatic hyperlactatemia/lactic acidosis had a significant increase in their F2-isoprostanes compared with subjects with asymptomatic sustained hyperlactatemia (0.082 +/- 0.021 vs. 0.053 +/- 0.021, respectively; P < 0.05).

Acidosis, Lactic↗
PubMed2006

Macrophages are essential for antitumour effects against weakly immunogenic murine tumours induced by class B CpG-oligodeoxynucleotides.

We explored the mechanisms of class B CpG-oligodeoxynucleotide-induced antitumour effects against weakly immunogenic tumours. Treatment with CpG-oligodeoxynucleotide 1826 (CpG) induced similar antitumour effects in B16 melanoma-bearing immunocompetent C57BL/6 mice and T-cell-deficient severe combined immunodeficient (SCID) mice, and NXS2 neuroblastoma-bearing T-cell-depleted A/J mice. Both macrophages (Mphi) and natural killer (NK) cells from CpG-treated C57BL/6 mice could mediate cytotoxicity in vitro, suggesting that these cell types might control tumour growth in vivo. However, CpG treatment of SCID/beige mice or T-cell-depleted and NK-cell-depleted A/J mice still induced antitumour effects in vivo, arguing against a major role of NK cells in the antitumour effects of CpG in the absence of T cells. In contrast, CpG treatment of interferon-gamma knockout (IFN-gamma(-/-)) C57BL/6 mice resulted in no antitumour effects in vivo and no Mphi-mediated tumoristasis in vitro despite unaltered cytolytic function of NK cells in vitro. Moreover, Mphi inactivation by silica substantially reduced CpG-induced suppression of tumour growth in vivo, revealing an important role of Mphi in CpG-induced antitumour effects. The in vitro tumouritoxicity by CpG-stimulated Mphi (CpG-Mphi) correlated with tumour cell mitochondria dysfunction and involved nitric oxide (NO), tumour necrosis factor-alpha (TNF-alpha) and IFN-gamma, whereas interleukin-1alpha (IL-1alpha), IL-1beta, IFN-alpha, TNF-related apoptosis-inducing ligand and Fas ligand played insignificant roles in CpG-Mphi tumouritoxicity. Taken together, our results indicate that the growth control of weakly immunogenic tumours during CpG-immunotherapy is mediated predominantly by Mphi, rather than T cells or NK cells.

Animals↗
PubMed2002

Endothelial cells maintain a reduced redox environment even as mitochondrial function declines.

Human umbilical vein endothelial cells (HUVECs) are an endothelial model of replicative senescence. Oxidative stress, possibly due to dysfunctional mitochondria, is believed to play a key role in replicative senescence and atherosclerosis, an age-related vascular disease. In this study, we determined the effect of cell division on genomic instability, mitochondrial function, and redox status in HUVECs that were able to replicate for approximately 60 cumulative population doublings (CPD). After 20 CPD, the nuclear genome deteriorated and the protein content of the cell population increased. This indicated an increase in cell size, which was accompanied by an increase in oxygen consumption, ATP production, and mitochondrial genome copy number and approximately 10% increase in mitochondrial mass. The antioxidant capacity increased, as seen by an increase in reduced glutathione, glutathione peroxidase, GSSG reductase, and glucose-6-phosphate dehydrogenase. However, by CPD 52, the latter two enzymes decreased, as well as the ratio of mitochondrial-to-nuclear genome copies, the mitochondrial mass, and the oxygen consumption per milligram of protein. Our results signify that HUVECs maintain a highly reducing (GSH) environment as they replicate despite genomic instability and loss of mitochondrial function.

Cells, Cultured↗
PubMed2025

Identification of mitophagy-related biomarkers with immune cell infiltration in psoriasis.

BACKGROUND: Psoriasis is an inflammatory disorder characterized by scaly erythematous plaques and significant comorbidities. Recent studies have suggested that impaired mitophagy, the cellular mechanism for removing dysfunctional mitochondria, may contribute to the pathogenesis of psoriasis. METHODS: In this study, we analyzed bulk RNA sequencing data from 167 healthy individuals and 177 patients with psoriasis obtained from the Gene Expression Omnibus database (GSE30999 and GSE54456). Mitophagy-related genes were isolated using weighted gene co-expression network analysis. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed and protein-protein interaction networks were constructed for the functional enrichment of genes associated with mitophagy. The correlations between genes associated with mitophagy, signaling pathways, and immune cell infiltration were analyzed. The potential diagnostic value of genes associated with mitophagy was evaluated using receiver operating characteristic (ROC) curves, which were validated in imiquimod-induced psoriatic skin lesions in mice. RESULTS: We identified 3,839 differentially expressed genes between healthy individuals and patients with psoriasis, and 23 genes were selected as hub genes showing a high correlation with mitophagy in psoriasis. GO and KEGG analyses revealed that hub and associated genes were significantly correlated with skin functions, such as epidermal development and keratinocyte differentiation. In addition, mitophagy-related genes were negatively associated with pro-inflammatory and pro-proliferation pathways in psoriasis. Among the immune cells, CD4+ T cells were most significantly affected by mitophagy-related genes. ROC analysis demonstrated that mitophagy-related genes, especially ACER1, C1ORF68, CST6, FLG2, GJB3, GJB5, GPRIN2, KRT2, and SPRR4 were potential biomarkers of psoriasis for use in diagnosis or treatment. CONCLUSIONS: Mitophagy-related genes play crucial roles in psoriasis and have potential use as biomarkers, providing insights into disease mechanisms and therapeutic targets. Further research may lead to the development of new strategies for psoriasis management.

Psoriasis↗
PubMed2005

Oxidative stress: the old enemy in Alzheimer's disease pathophysiology.

The complex nature and genesis of oxidative damage in Alzheimer disease can be partly answered by mitochondrial and redox-active metal abnormalities. By releasing high levels of hydrogen peroxide, dysfunctional mitochondria propagate a series of interactions between redox-active metals and oxidative response elements. In the initial phase of disease development, amyloid-beta deposition and hyperphosphorylated tau may function as compensatory responses and downstream adaptations to ensure that neuronal cells do not succumb to oxidative injuries. However, during the progression of the disease, the antioxidant activity of both agents evolves into pro-oxidant activity representing a typical gain-of-function transformation, which can result from an increase in reactive species and a decrease in clearance mechanisms.

Alzheimer Disease↗
PubMed2003

Diabetes activates cell death pathway after transient focal cerebral ischemia.

It is well known that diabetes aggravates brain damage in experimental and clinical stroke subjects. Diabetes accelerates maturation of neuronal damage, increases infarct volume, and induces postischemic seizures. The mechanism by which diabetes increases ischemic brain damage is still elusive. Our previous experiments indicate that mitochondria dysfunction may play a role in neuronal death. The objective of this study is to determine whether streptozotocin-induced diabetes activates cell death pathway after a brief period of focal cerebral ischemia. Both diabetic and nondiabetic rats were subjected to 30 min of transient middle cerebral artery occlusion, followed by 0, 0.5, 3, and 6 h of reperfusion. We first determined the pathological outcomes after 7 days of recovery by histopathology, and then detected key components of programmed cell death pathway using immunocytochemistry coupled with confocal laser-scanning microscopy and Western blot analysis. The results show that the cytosolic cytochrome c increased mildly after reperfusion in nondiabetic samples. This increase was markedly enhanced in diabetic rats in both ischemic focus and penumbra. Subsequently, caspase-3 was activated and poly-ADP ribose polymerase (PARP) was cleaved. Our results suggest that activation of apoptotic cell death pathway may play a pivotal role in exaggerating brain damage in diabetic subjects.

Animals↗
PubMed2005

Effects of polyphyllin D, a steroidal saponin in Paris polyphylla, in growth inhibition of human breast cancer cells and in xenograft.

Paris polyphylla is a traditional Chinese Medical herb that has been used in treating cancer for thousands of year. Without studies on the anticancer effects of Paris polyphylla being initiated before, we have first studied the component of Paris polyphylla and have spotted out a steroidal saponin, polyphyllin D. As long as the chemical structure and the improved synthesis of polyphyllin D were ascertained, both in vitro to in vivo studies were performed. It was found that treatment of MCF-7 and MDA-MB-231 cells with polyphyllin D resulted in the inhibition of viability and induction of apoptosis in a dose-dependent manner, with an IC50 of 5 microM and 2.5 microM, respectively, after 48 hours of incubations. Apoptosis of MCF-7 and MDA-MB-231 cells by polyphyllin D was evidenced by the occurrence of DNA fragmentation, formation of a hypodiploid peak in the cell cycle analysis, phosphatidyl-serine externalization and a late loss of membrane integrity. Mechanistically, polyphyllin D dissipates the mitochondrial membrane potential, induces a downregulation of anti-apoptotic Bcl-2 expression and an up-regulation of pro-apoptotic Bax expression, and activates caspase-9. These results suggest that polyphyllin D elicits apoptosis through mitochondria dysfunction. In vivo study demonstrated that daily administration of polyphyllin D (2.73 mg/kg body weight) through intravenous injection for ten days in nude mice bearing MCF-7 cells effectively reduced tumor growth for 50% in terms of tumor weight and size, given no significant toxicity in heart and liver to the host. All these findings provide novel insights that polyphyllin D could serve as a candidate in breast cancer treatment.

Animals↗
PubMed1993

[Change in calcium transport as a factor in causing dysfunction of myocardial mitochondria during hypoxia].

During normoxic incubation of isolated myocardial mitochondria, there were marked increases in mitochondrial calcium when free calcium concentration in the incubation medium was enhanced. The increases were concomitant with rises increase in the rate of state 4 respiration. Moreover, there is a positive correlation between the mitochondrial calcium and the rate of state 4 respiration. During hypoxic incubation, when the calcium concentration of the incubation medium was enhanced, there was no significant increase in mitochondrial calcium and the rises in the rate of state 4 respiration were much lower than the rises during normoxia. Hypoxic incubation in medium of low calcium concentration (pCa 8.0) resulted in slight rises in rate of state 4 respiration. The above results suggest that in myocytes, the mitochondrial dysfunction under hypoxia may be caused indirectly by changes in cytoplasm rather than directly by hypoxia. It seems that the change of cellular free calcium concentration is an important factor in the mitochondrial dysfunction.

Animals↗
PubMed2005

Biochemical dysfunction in heart mitochondria exposed to ischaemia and reperfusion.

Heart tissue is remarkably sensitive to oxygen deprivation. Although heart cells, like those of most tissues, rapidly adapt to anoxic conditions, relatively short periods of ischaemia and subsequent reperfusion lead to extensive tissue death during cardiac infarction. Heart tissue is not readily regenerated, and permanent heart damage is the result. Although mitochondria maintain normal heart function by providing virtually all of the heart's ATP, they are also implicated in the development of ischaemic damage. While mitochondria do provide some mechanisms that protect against ischaemic damage (such as an endogenous inhibitor of the F1Fo-ATPase and antioxidant enzymes), they also possess a range of elements that exacerbate it, including ROS (reactive oxygen species) generators, the mitochondrial permeability transition pore, and their ability to release apoptotic factors. This review considers the process of ischaemic damage from a mitochondrial viewpoint. It considers ischaemic changes in the inner membrane complexes I-V, and how this might affect formation of ROS and high-energy phosphate production/degradation. We discuss the contribution of various mitochondrial cation channels to ionic imbalances which seem to be a major cause of reperfusion injury. The different roles of the H+, Ca2+ and the various K+ channel transporters are considered, particularly the K+(ATP) (ATP-dependent K+) channels. A possible role for the mitochondrial permeability transition pore in ischaemic damage is assessed. Finally, we summarize the metabolic and pharmacological interventions that have been used to alleviate the effects of ischaemic injury, highlighting the value of these or related interventions in possible therapeutics.

Animals↗
PubMed2003

All-trans retinoic acid (atRA) differentially induces apoptosis in matched primary and metastatic melanoma cells -- a speculation on damage effect of atRA via mitochondrial dysfunction and cell cycle redistribution.

All-trans retinoic acid (atRA) has been suggested to exert its cytotoxicity via apoptosis but the mechanisms behind the damage effects have not been fully understood. In this study, we investigated the cytotoxic effects of atRA in eleven primary and matched metastatic cutaneous melanoma cell lines. All the primary and metastatic melanoma cell lines examined expressed the retinoic acid receptors. The cultured melanoma cells treated with atRA showed dysfunction of mitochondria and altered cell cycle distribution, inhibited cell proliferation and apoptosis. The cytotoxic effects of atRA were dose- and time-dependent. The dysfunction of mitochondria and induction of apoptosis were more pronounced in the primary tumor cells than in the metastatic cell lines from the same patients. The data indicate that the cytotoxic effect of atRA was mediated through dysfunction of mitochondria, alterations in cell cycle and induction of apoptosis. Melanoma in early stage may have better response to atRA adjuvant therapy than the melanoma in late stage, suggesting the early utility of atRA in melanoma chemotherapy.

Apoptosis↗
PubMed2003

Proteomic analysis of cancer-cell mitochondria.

Mitochondrial dysfunction and mutations in mitochondrial DNA have been frequently reported in cancer cells. Mitochondrial gene-expression signatures of transformed cells have been identified; however, the phenotypic effects of these genetic alterations remain to be established. Identification of mitochondrial proteins that are aberrantly expressed in cancer cells has been made possible by the recent development of mitochondrial functional proteomics and could identify new markers for early detection and risk assessment, as well as targets for therapeutic intervention.

Humans↗
PubMed2002

Complexities in ETS-domain transcription factor function and regulation: lessons from the TCF (ternary complex factor) subfamily. The Colworth Medal Lecture.

The ETS-domain transcription factor family can be divided into a series of subfamilies. Elk-1 represents the founding member of the ternary complex factor (TCF) subfamily. By focusing on the TCF subfamily, we can demonstrate the complexities that exist in the function and regulation of ETS-domain transcription factors. This article focuses on Elk-1 in detail and summarizes the functions of other TCFs. The key themes covered include the domain structure of the TCFs, the mechanisms of complex formation with serum response factor, regulation of TCFs by mitogen-activated protein kinase cascades, and transcriptional regulatory properties of the TCFs. Finally, the emerging role of the TCFs in vivo is discussed. A picture is developing indicating that, while these proteins exhibit significant sequence and functional conservation, key differences in their structure and regulation are being identified which may relate to unique functions of these proteins in vivo.

Amino Acid Sequence↗
PubMed1994

Dysfunction of mouse liver mitochondria induced by 2,2'-azobis-(2-amidinopropane) dihydrochloride, a radical initiator, in vitro and in vivo.

Mouse liver mitochondria were uncoupled in a time dependent by intraperitoneal injection of a radical initiator, 2,2'-azobis-(2-amidinopropane) dihydrochloride (AAPH) (100 mg/kg). State 3 respiration, ADP/O ratio and respiratory control ratio (RCR) were decreased 30 min after injection but there was no effect on state 4 respiration. Lipid peroxidation was increased and oxidative phosphorylation was uncoupled at one hr after drug injection but gradually recovered to normal levels after 14 hr in vivo. State 3 respiration, RCR and ADP/O ratio but not state 4 respiration of isolated mouse mitochondria were inhibited by short term incubation with AAPH in vitro. This inhibitory action was concentration dependent (ID50 = 5 mM) but was not prevented by alpha-tocopherol. AAPH had no effect on electron transport or the membrane potential of these isolated mitochondria. However, mitochondria were uncoupled via lipid peroxidation and swelling by long term incubation with AAPH. These inhibitory effects of AAPH were reduced by its spontaneous degradation not only in vitro but also in vivo. Thus AAPH induces mitochondrial dysfunction by direct action in the early period of treatment and free radicals produced from AAPH mediate mitochondrial swelling via lipid peroxidation in the late period. From these findings, it is concluded that mitochondrial phosphorylation plays an important role in the pathogenesis of liver injury induced by AAPH and that radicals generated by AAPH might be a source of liver injury and mitochondrial dysfunction in vivo.

Amidines↗
PubMed1990

Reduction of phosphate-induced dysfunction in rat heart mitochondria by carnitine.

The direct effects of varying concentrations (5-40 mM) of D,L-carnitine were studied in two populations, subsarcolemmal and interfibrillar, of cardiac mitochondria exposed to inorganic phosphate (Pi). After 5 min preincubation 20 mM Pi significantly depressed oxidative phosphorylation rate and ADP/ATP translocase activity, in both populations. Inclusion of D,L-carnitine during preincubation significantly prevented the Pi-induced depression in oxidative phosphorylation without affecting the ADP/ATP translocate system. The Pi-induced inhibition in mitochondrial oxygen consumption rate was seen with either pyruvate-malate, glutamate-malate or succinate as respiratory substrates and was also observed in uncoupled mitochondria treated with 2,4-dinitrophenol. Mitochondrial swelling and shrinkage studies revealed Pi-induced inner membrane instability, a phenomenon prevented by D,L-carnitine in a dose-dependent manner. The effect of Pi was also observed at a concentration of 5 mM which was also prevented by carnitine. Mepacrine, a phospholipase A2 inhibitor, failed to prevent any of the effects of Pi. The results therefore suggest that Pi can produce a depression in mitochondrial oxidative phosphorylation through a mechanism possibly associated with disturbed inner membrane structure and function but apparently unrelated to phospholipase A2 activation. The salutary actions of carnitine may partly explain its protective effects in the ischemic and reperfused heart, a phenomenon associated with enhanced intracellular Pi accumulation.

Animals↗
PubMed2004

Metabolic dysfunction and depletion of mitochondria in hearts of septic rats.

Our previous studies indicate that hearts from septic rats have decreased work with oxygen wasting. The present studies test if there is energy deficit, changes in cardiac mitochondrial content and caspase activation during sepsis. Anesthetized, male Sprague-Dawley rats received no surgical treatment (control), laparotomy (sham), or laparotomy with cecal ligation and puncture (CLP) to induce polymicrobial septic shock. Hearts were isolated 12-14 h later. Cardiac work, oxygen consumption, substrate oxidation and energy stores were measured in perfused hearts. Normalized density of mitochondria was determined in ventricles without perfusion by morphometric analysis with electron microscopy. Citrate synthase activity was assessed in homogenates and isolated mitochondria. Cardiac work decreased significantly in CLP (47%), while oxygen consumption and glucose oxidation were unchanged compared with control or sham hearts (oxygen and substrate wasting). Tissue adenosine triphosphate, creatine phosphate and glycogen were lower in CLP hearts (energy deficit). Mitochondrial grid intersects decreased significantly from 151 +/- 8 sham to 130 +/- 4 CLP out of 361 possible intersects and autophagy was observed in CLP hearts. Total activity of citrate synthase decreased in homogenates (99 +/- 8 micromol/min/g wet weight sham vs. 62 +/- 7 CLP, P < 0.05) and in the mitochondrial fraction (27 +/- 1 micromol/min/g wet weight sham to 22 +/- 1 CLP, P < 0.05). Calculated mitochondrial content decreased from 63 +/- 4 mg protein/g wet weight sham to 46 +/- 5 CLP, P < 0.05 (mitochondrial depletion). Caspase-3 activity doubled and tumor necrosis factor alpha content tripled in CLP hearts. CONCLUSIONS. - Oxygen and substrate wasting in CLP occurs with fewer mitochondria and energy deficit, processes that are coincident with caspase-3 activation.

Animals↗
PubMed2002

Dysfunction of rat liver mitochondria by selenite: induction of mitochondrial permeability transition through thiol-oxidation.

Selenium is an essential trace element in mammals and is thought to play a chemopreventive role in human cancer, possibly by inducing tumor cell apoptosis. Mitochondria play a pivotal role in the induction of apoptosis in many cell types. The effects of selenite on mitochondrial function were therefore investigated. Selenite induced the oxidation and cross-linking of protein thiol groups, mitochondrial permeability transition (MPT), a decrease in the mitochondrial membrane potential, and the release of cytochrome c in mitochondria isolated from rat liver. Induction of the MPT by selenite was prevented by cyclosporin A, EGTA, or N-ethylmaleimide. These results thus indicate that selenite induces the MPT as a result of direct modification of protein thiol groups, resulting in the release of cytochrome c and a loss of mitochondrial membrane potential.

Animals↗