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At least 73 records · Page 4Linked to original sources
PubMed1990

Intraocular pressure effects on optic nerve-head oxidative metabolism measured in vivo.

The effects of acute intraocular pressure (IOP) on the reduction/oxidation ratio of cytochrome a, a3 were measured from intact cat optic nerve by microfiber reflection spectrophotometry. This enabled the real-time analysis of optic nerve-head oxidative metabolism following IOP or mean arterial pressure (MAP) changes. Findings included: (1) cytochrome a, a3 became more reduced and relative blood volume decreased at lower perfusion pressures, even at IOP of less than 20 mm Hg; (2) metabolic inhibition began at variable perfusion pressures but invariably progressed as perfusion pressure declined; and (3) increased IOP or decreased MAP caused metabolic inhibition. These findings demonstrate that: (1) optic nerve metabolic dysfunction is possible at low IOPs; (2) lowering IOP can reverse metabolic dysfunction; (3) the metabolic response is dependent on IOP and/or MAP changes; and (4) the metabolic inhibition is related to optic nerve ischemia.

Animals↗
PubMed2025

C6ORF120 regulates hepatic lipid metabolism through PPAR signaling pathway in metabolic dysfunction-associated steatotic liver disease.

Background Emerging evidence indicates that C6ORF120 is highly expressed in the liver and may modulate immune responses in various hepatic disorders. However, its role in hepatic lipid metabolism and metabolic dysfunction-associated steatotic liver disease (MASLD) is unexplored. This study aimed to elucidate the effects and potential mechanisms of C6ORF120 on hepatic lipogenesis. Methods C6ORF120 expression in MASLD was assessed using patient serum and the Gene Expression Omnibus (GEO) database. A high-fat diet-induced MASLD model was established in C6orf120-KO rats. Fatty acid-induced lipid accumulation models were generated in primary hepatocytes, HepG2 and Huh7 cells. These models were employed to investigate the effects of C6ORF120 on hepatic lipogenesis and MASLD progression. Results C6ORF120 expression was significantly upregulated in MASLD patients and obese rat models. Genetic deletion of C6ORF120 markedly alleviated high-fat diet-induced steatosis in the liver of rats. In vitro, C6orf120 gene deficiency attenuated lipid accumulation and suppressed key lipogenic genes (such as fatty acid synthase (Fasn), phospho-acetyl coenzyme carboxylase (p-ACC), sterol regulatory element binding protein-1c (Srebp1c)) in primary hepatocytes and HepG2 cells. Conversely, C6ORF120 overexpression increased lipid accumulation in HepG2 cells. RNA sequencing analysis showed that lipid metabolism pathway and peroxisome proliferators activated receptor (PPAR) signaling pathway were significantly altered in the liver of C6orf120-KO rats. We demonstrated that C6ORF120 may regulate lipid metabolism through the hepatic PPARα, which is involved in fatty acid production and lipid oxidation. Further, we found that serum C6ORF120 expression was correlated with clinical indicators in patients with MASLD. Conclusion This study preliminarily revealed a novel function for C6ORF120 in hepatic lipid metabolism via affecting the PPAR pathway. The result identifies C6ORF120 as a novel regulator of hepatic lipid metabolism through PPARα-dependent mechanisms, offering potential therapeutic targets for MASLD.

Lipid Metabolism↗
PubMedDate not supplied

Audiologic and metabolic findings in 90 patients with fluctuant hearing loss.

Fluctuant hearing loss is a common occurrence. It is difficult to diagnose in its early stages when hearing thresholds are near normal and the only complaints the patient has are of fullness and tinnitus. Audiologic tests are helpful in confirming the diagnosis. Impedance measurements are an accurate assessment of middle ear status and can assist in localizing the fullness experienced by these patients. Site of lesion tests and discrimination scores at various sensation levels are sensitive indexes of disease activity. Observations during medical treatment of 90 patients with metabolic dysfunction (hyperlipoproteinemia: hypoglycemia; hypothyroidism) suggest that discrimination scores fluctuate more widely than do pure tone thresholds over a period of time. Thirty patients were given complete audiologic testing after dietary management and treatment. All reported relief from tinnitus and fullness, and 15 or 50% showed improved audiograms and discrimination scores. Any change in the energy reserve or metabolic rate of the inner ear by a systemic metabolic dysfunction can contribute to or cause sensorineural hearing loss. Energy flow from metabolic sources is needed to transduce the acoustic stimuli into neural excitation patterns. The presence of any systemic metabolic dysfunction can be expected to contribute to and cause fluctuant hearing loss.

Auditory Threshold↗
PubMed1995

Identification of hibernating myocardium: a comparison between dobutamine echocardiography and study of perfusion and metabolism in patients with severe left ventricular dysfunction.

The distinction between fibrotic and viable myocardium is a key issue in patients with coronary artery disease and left ventricular dysfunction. Metabolic imaging with positron emission tomography (PET) and labeled tracers, along with the study of myocardial perfusion, is now available to identify hibernating myocardium. However, PET imaging of myocardial metabolism is a high-cost and time-consuming technique, and requires an on-site cyclotron. The aim of this study is to test the reliability of dobutamine echocardiography (DE) compared with PET imaging, for the identification of hibernating myocardium. In 16 patients, scheduled for myocardial revascularization, left ventricular shapes were divided in eight segments both for echocardiographic and nuclear study evaluation. All patients underwent a technetium 99m MIBI single-photon emission tomography stress-rest study of perfusion, a fluorine-18-labeled deoxyglucose (FDG(/PET study of metabolism, and a DE test (baseline, at a 5 micrograms/kg/min infusion of dobutamine for 8 minutes and at a 10 micrograms/kg/min dose for additional 8 minutes). Neither myocardial ischemia nor arrhythmia occurred during the DE test. Baseline echocardiograms showed 90 segments with wall motion abnormalities: wall motion impairment was decreased or reversed in 33 of 90 segments; it remained unchanged in 57 of 90 segments. In 32 of 33 segments considered viable on the basis of DE and in 21 of 57 segments with unchanged kinesis, some degree of FDG was detected. Thus, sensitivity and specificity of DE compared with nuclear studies was 60% and 97% respectively. Moreover, a good correlation and agreement (kappa = 0.51) between DE and the presence of FDG were found. We conclude that DE is a safe and reliable test for the screening of hibernating myocardium in patients with chronic coronary artery disease and left ventricular dysfunction.

Coronary Disease↗
PubMed1994

[Dynamics of changes in lipid metabolism during the first year after kidney transplantation].

Dyslipidemia is one of the first metabolic dysfunction observed among patients with end stage renal disease. It can also induce acceleration of renal tissue damage. Kidney transplantation may cause recovery of some dysfunction in lipid metabolism while influencing deterioration of others. The aim of this study was to monitor dynamics of basic lipid parameters in the first year after kidney transplantation. The sample included 25 patients (9W, 16M), aged 18-59, avg. 36. We have measured concentration of the following parameters in blood serum: triglycerides (TG), total cholesterol (CH-C) and apolipoprotein B (Apo B). Simultaneously, functions of transplanted kidney were tested with use of routine methods. The immunosuppressive treatment of patients followed the scheme: cyclosporine + prednisolone + azathioprine. The treatment influence on lipid disorders was measured by relevant correlation coefficients. The obtained results point to the observation that in the first year after kidney transplantation the TG concentration gradually decreases, with simultaneous continuous increase of CH-C concentration, mainly due to LDL concentration increase. No influence of immunosuppressive treatment on lipid parameters was observed. However, lipid dysfunction, especially TG, correlated with kidney function.

Adolescent↗
PubMed1994

Neural dysfunction and metabolic imbalances in diabetic rats. Prevention by acetyl-L-carnitine.

The rationale for these experiments is that administration of L-carnitine and/or short-chain acylcarnitines attenuates myocardial dysfunction 1) in hearts from diabetic animals (in which L-carnitine levels are decreased); 2) induced by ischemia-reperfusion in hearts from nondiabetic animals; and 3) in nondiabetic humans with ischemic heart disease. The objective of these studies was to investigate whether imbalances in carnitine metabolism play a role in the pathogenesis of diabetic peripheral neuropathy. The major findings in rats with streptozotocin-induced diabetes of 4-6 weeks duration were that 24-h urinary carnitine excretion was increased approximately twofold and L-carnitine levels were decreased in plasma (46%) and sciatic nerve endoneurium (31%). These changes in carnitine levels/excretion were associated with decreased caudal nerve conduction velocity (10-15%) and sciatic nerve changes in Na(+)-K(+)-ATPase activity (decreased 50%), Mg(2+)-ATPase (decreased 65%), 1,2-diacyl-sn-glycerol (DAG) (decreased 40%), vascular albumin permeation (increased 60%), and blood flow (increased 65%). Treatment with acetyl-L-carnitine normalized plasma and endoneurial L-carnitine levels and prevented all of these metabolic and functional changes except the increased blood flow, which was unaffected, and the reduction in DAG, which decreased another 40%. In conclusion, these observations 1) demonstrate a link between imbalances in carnitine metabolism and several metabolic and functional abnormalities associated with diabetic polyneuropathy and 2) indicate that decreased sciatic nerve endoneurial ATPase activity (ouabain-sensitive and insensitive) in this model of diabetes is associated with decreased DAG.

Acetylcarnitine↗
PubMed1989

Efficacy of antithrombin III supplementation in animal models of fulminant Escherichia coli endotoxemia or bacteremia.

Plasma antithrombin III (ATIII) levels decrease early during gram-negative septicemia, and even a moderate decrease in this major inhibitor of the coagulation system is associated with serious disseminated intravascular coagulation (DIC). Herein the efficacy of high-dose (at least 250 units/kg) ATIII supplementation in animal models of Escherichia coli endotoxemia or bacteremia is reported. An endotoxemic rat model demonstrated that: (1) DIC occurs very early, before the appearance of deleterious cardiovascular abnormalities; (2) ATIII prophylaxis attenuates DIC, metabolic dysfunction, and organ damage; (3) ATIII prophylaxis increases permanent survival; (4) ATIII treatment one hour after endotoxin challenge attenuates DIC, metabolic dysfunction, and organ damage, although not as well as when given prophylactically, and survival is not increased. An endotoxemic sheep pulmonary dysfunction model demonstrated that: (1) ATIII prophylaxis prevents the typical decrease in arterial oxygen partial pressure; (2) ATIII prophylaxis combined with alpha-1-proteinase inhibitor significantly attenuates indices of pulmonary dysfunction. An E. coli bacteremic baboon model demonstrated that ATIII prophylaxis and treatment significantly attenuate indices of DIC and organ damage and prevent death in an otherwise completely lethal dose bacterial challenge. In conclusion, prophylactic treatment with high doses of ATIII may be efficacious in disease states of impending disseminated intravascular coagulation, such as primary or secondary gram-negative septicemia.

Animals↗
PubMedDate not supplied

Disparate recovery of resting and stimulated oxidative metabolism following transient ischemia.

To assess the residual effects of transient cerebral ischemia on mitochondrial oxidative metabolic function, changes in the reduction/oxidation state of cytochrome a,a3 and relative local blood volume were measured in situ from the exposed cerebral surface of rat brain before and after 10 minutes of carotid artery ligation. During the ischemic interval, cytochrome a,a3 became reduced and electrocortical activity was abolished. During the first 20 minutes of reperfusion cytochrome a,a3 was hyperoxidized beyond baseline with eventual recovery to the original steady state. Electrocortical activity returned more slowly. Increased energy demand induced by electrical stimulation of the cortex produced transient oxidation of cytochrome a,a3. The amplitude of this oxidative response was decreased during the first 30 minutes of reperfusion. During the first 2 hours of reperfusion the time required for re-reduction of the oxidative response was lengthened despite the recovery of baseline mitochondrial redox state. These data demonstrate residual metabolic dysfunction after transient ischemia not apparent under "resting" conditions but evident when the system is required to perform additional "work." We speculate this metabolic dysfunction could be due to relative substrate limitation.

Animals↗
PubMed1981

Disorders of glutamate metabolism and neurological dysfunction.

Disorders of glutamate metabolism are associated with profound alteration of CNS function. Although the precise biochemical mechanisms responsible for nervous system dysfunction in most of these disorders are unknown, it can be concluded that biochemical aberrations in the metabolism of glutamate usually result in malfunction of the CNS. As with most disorders of amino acid metabolism that are associated with brain dysfunction, the molecular mechanisms underlying pathogenesis of these disorders remain obscure. Why do some biochemically affected individuals remain free of significant neurological involvement? The explanation that the accumulation of a specific metabolite is responsible for the pathogenesis of a disease process does not answer this and may frequently prove to be incorrect. More complete descriptions of these disorders of glutamate metabolism and their attendant neurological dysfunction will be required before any firm linkage between the biochemical defects and the clinical manifestations of the disease processes can be established. In addition, a much greater knowledge of the control mechanisms regulating glutamate metabolism in the CNS will be needed before the complexities of these disorders can be fully understood. Finally, the dual role of glutamate metabolites as intermediates in crucial pathways of metabolism and as neurotransmitters modulating electrical signals stresses the complexity and importance of glutamate metabolism in CNS function.

Amino Acid Metabolism, Inborn Errors↗
PubMed1994

Delayed tumor necrosis factor alpha blockade attenuates pulmonary dysfunction and metabolic acidosis associated with experimental gram-negative sepsis.

OBJECTIVE: To ascertain the effect of delayed tumor necrosis factor alpha (TNF-alpha) on the evolution of systemic and pulmonary injury after the onset of sepsis. DESIGN: Prospective controlled trial. INTERVENTION: Anesthetized swine were made septic with a 1-hour infusion of live Pseudomonas aeruginosa, following which a treatment group received an infusion of anti-TNF-alpha monoclonal antibody (5 mg/kg). Control animals received 0.9% saline. RESULTS: Delayed anti-TNF-alpha treatment had no effect on septic pulmonary hypertension or decline in cardiac output. Late recovery in systemic arterial hypotension was associated with a reversal of arterial acidosis (P < .05 by t test and analysis of variance with Tukey's Studentized Range Test) compared with unprotected septic animals. Septic animals had a significant increase in mean (+/- SEM) plasma lactate levels at 5 hours compared with baseline values (3.8 +/- 0.7 vs 2 +/- 0.4, P < .05), but remained unchanged from baseline following anti-TNF-alpha treatment (1.5 +/- 0.1 vs 1.6 +/- 0.2, not significant). Characteristic septic neutropenia was dramatically reversed by anti-TNF-alpha treatment and was associated with downregulation (P < .05 by t test and analysis of variance) of polymorphonuclear neutrophil (PMN) leukocyte CD18 adhesion receptors and reduction (P < .05 by t test and analysis of variance) in lung PMN sequestration measured by myeloperoxidase activity. The mean (+/- SEM) decrease in bronchoalveolar lavage protein indicated an attenuated permeability injury in anti-TNF-alpha animals (septic animals at 5 hours compared with baseline value, 1044 +/- 270 vs 149 +/- 28 micrograms/mL; control animals at 5 hours compared with baseline value, 217 +/- 83 vs 129 +/- 19 micrograms/mL; P < .05 by t test and analysis of variance). CONCLUSIONS: These data show that delayed anti-TNF-alpha treatment reversed metabolic acidosis associated with sepsis. Furthermore, anti-TNF-alpha treatment reversed septic neutropenia, reduced PMN sequestration, and was associated with attenuated lung injury in a model of fulminant sepsis. This supports evidence of PMN-mediated tissue injury in sepsis and suggests mechanisms for potential therapeutic benefit of anti-TNF-alpha treatment in clinical practice.

Acidosis, Lactic↗
PubMed1993

Effects of K+ channel openers on ischemic dysfunction and metabolic disturbance in isolated perfused rat heart.

The effects of two structurally different K+ channel openers, KRN2391 and cromakalim, on cardiac mechanisms during ischemia and reperfusion were studied in isolated perfused rat hearts. Isolated buffer-perfused rat hearts pretreated with KRN2391, cromakalim and vehicle were subjected to 25 min of ischemia followed by 30 min of reperfusion. Before ischemia, KRN2391 (1-10 microM) and cromakalim (1-10 microM) increased coronary flow, but did not modify cardiac function or biochemical parameters (adenine nucleotides, energy charge potential: ECP, lactate). During ischemia, KRN2391 (3, 10 microM) and cromakalim (10 microM) significantly accelerated the reduction in cardiac function and attenuated the decreased levels of ATP and ECP, but did not change the lactate content. After 30 min of reperfusion, pretreatment with KRN2391 and cromakalim resulted in a significant improvement in cardiac function, ischemic contracture and biochemical parameters. Thus, both KRN2391 and cromakalim have beneficial effects on biochemical parameters during ischemia and reperfusion, effects which may be related to cardiodepression during ischemia.

Animals↗
PubMed1991

Contractile dysfunction during metabolic acidosis: role of impaired energy metabolism.

To investigate the mechanisms by which acidosis depresses cardiac function, a Langendorff isolated perfused rat heart preparation was studied using 31P magnetic resonance spectroscopy. Isolated hearts were subjected to normal perfusion conditions or experimental manipulations simulating severe metabolic acidosis, substrate depletion, impairment of oxidative metabolism, or low perfusate calcium concentrations. All maneuvers resulted in marked reductions in oxygen consumption and the force of myocardial contraction (dP/dt). Metabolic acidosis had bioenergetic changes suggestive of impaired energy production, specifically, increases in Pi and decreases in phosphocreatine concentrations, which did not occur in hearts subjected to low perfusate calcium concentrations. In acidotic perfusions as well as substrate depletion and impairment of oxidative metabolism, the change in dP/dt correlated best with the change in the intracellular concentration of monovalent Pi (P(im)) (r = 0.70, P less than 0.01), whereas in hearts subjected to a low perfusate calcium concentration, there was no relationship between dP/dt and the change in Pim concentrations. More detailed analysis of the time course of the metabolic and physiological changes with metabolic acidosis revealed a discordance between changes in Pim and the decreases in dP/dt during the first 20 min of the induction of acidosis and the first 10 min of recovery from acidosis. These data suggest that metabolic acidosis has a major direct effect on energy metabolism in this model. Moreover, impairment of oxidative metabolism in concert with decreases in intracellular pH may be important in the contractile failure associated with prolonged metabolic acidosis.

Acidosis↗
PubMed1992

[Autonomic dysfunction in metabolic diseases].

Among many metabolic disorders, porphyrias and Fabry disease are known to affect autonomic nervous system. In patients with acute intermittent porphyria, hereditary coproporphyria, and variegate porphyria, autonomic symptoms such as abdominal pain, vomiting, hypertension and tachycardia are among the most prominent clinical manifestations. Fabry disease is clinically characterized by severe limb pain, hypohidrosis, angiokeratomas and various autonomic symptoms. In both porphyrias and Fabry disease, pathological changes in the central and peripheral autonomic nervous system have been documented. In porphyrias, a loss of myelinated fibers, axonal degeneration, and segmental demyelination in peripheral autonomic nerves as well as chromatolysis of several brain stem nuclei have been found. In Fabry disease, abnormal amount of the substrates of alpha-galactosidase, i.e. ceramide di- and trihexoside, are found to be accumulated in the central and peripheral autonomic nerves.

Autonomic Nervous System Diseases↗
PubMed1992

[Diabetic cardiopathy. Pathophysiologic concepts and therapeutic approaches].

Epidemiological data reviewed suggest that diabetes itself increases the cardiac risk of diabetics (types I and II), independently from the development of coronary heart disease and in addition to other risk factors (hypertension, hypercholesterolemia, hypertriglyceridemia, smoking and others), presumably by a specific myocardial disease called "diabetic cardiopathy", or according to the recommendations of the WHO, "diabetic heart muscle disease." Disturbances of the left and right ventricular function as well as the autonomic function of the heart can be understood as signs of this specific cardiopathy. The pathophysiological mechanisms underlying this disease are not yet fully known; however, recent evidence is presented that diabetes leads to a facet of metabolic dysfunctions regarding glucose and energy metabolism, calcium homeostasis and the expression of specific proteins that diminish the ability of the heart to respond to increased workload and increase the vulnerability of the heart in diabetes. Since preliminary experimental data indicate that inhibitors of the angiotensin-converting enzyme can protect the heart in diabetes, it is intriguing to suggest that increased release of angiotensin II plays a significant role in the change from reduced adaptability to irreversible damage of the heart in diabetes.

Angiotensin-Converting Enzyme Inhibitors↗