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PubMedDate not supplied

Pathophysiology of cancer cachexia.

Cancer cachexia is a frequent complication observed in patients with malignant tumors. Although several decades have passed since the first focus on the metabolic dysfunction's associated with cancer, few effective therapeutic interventions have been successfully introduced into the medical armamentarium. The present study thoroughly reviews the basic pathophysiology of cancer cachexia and the treatment options already investigated in that field. Experimental and clinical studies were evaluated individually in order to clarify the intricate alterations observed in tumor-bearing patients. The difficulties in introducing sound and effective nutritional support or metabolic manipulation to reverse cancer cachexia are outlined in this review.

Animals↗

PubMed2025

Immune dysfunction in Alzheimer disease.

Emerging evidence highlights the crucial role of peripheral immune cells in maintaining brain homeostasis and their influence on the pathology of Alzheimer disease (AD). Genome-wide association studies have identified numerous AD risk variants in genes expressed by immune cells, implicating innate and adaptive immune pathways in disease progression. Advances in neuroimmunology have revealed that immune cell crosstalk involving T cells, B cells, monocytes and/or macrophages and neutrophils can modulate the hallmark features of AD, including amyloid plaque accumulation, tau pathology and chronic neuroinflammation. Mechanistic insights suggest that chronic peripheral inflammation, immune exhaustion, metabolic dysfunction and epigenetic reprogramming exacerbate neurodegeneration in AD by promoting toxic inflammation and impairing protein clearance in the brain. These findings may catalyse the development of novel immunomodulatory strategies, such as immune checkpoint inhibition and cytokine targeting, among others, for AD. This Review examines peripheral immune alterations in AD, evaluates related therapeutic opportunities and highlights key knowledge gaps, particularly the need for human-derived data to advance translational progress. Future research should prioritize personalized approaches that integrate genetic risk, immune profiling and ageing to inform next-generation therapies for AD.

Humans↗

PubMed1983

Periodic EEG discharges in psychiatry.

Periodic EEG discharges are signs of severe CNS dysfunction. In psychiatry they usually indicate presenile dementia of the Jacob-Creutzfeldt type. Psychiatric patients are presented in whom the occurrence and EEG features of diffuse and lateralized periodic discharges are discussed. It appears that toxic conditions other than acute barbiturate intoxication, such as drug withdrawal states and psychotropic drug overdosage, represent important etiological factors for inducing periodic EEG discharges. Their relation to clinical signs such as epileptic symptoms, metabolic dysfunction, and disturbance of consciousness is particularly stressed and related to current literature data.

Adult↗

PubMed2026

Diagnostic utility of fasting versus non-fasting blood glucose: contextualising testing strategies-a narrative review.

Diabetes mellitus is a chronic metabolic disorder characterised by impaired glucose homeostasis, resulting in persistent hyperglycaemia. Accurate and prompt diagnosis is essential for early intervention and prevention of long-term complications. Fasting blood glucose levels have traditionally been central to the diagnosis and monitoring of diabetes mellitus. However, growing evidence highlights the clinical relevance of non-fasting glucose measures, including postprandial glucose, random plasma glucose, and glycated haemoglobin (HbA1c) levels. Practical challenges, safety concerns, and evolving insights into glucose physiology have prompted renewed interest in flexible and context-driven approaches to glucose testing. This narrative review examines the physiological basis of fasting and non-fasting glucose regulation and critically evaluates their roles in diabetes screening, diagnosis, and monitoring. It also discusses the strengths and limitations of measuring fasting blood glucose, oral glucose tolerance, HbA1c, random plasma glucose, postprandial glucose, and continuous glucose monitoring. Special attention is given to pre-analytical and practical considerations, patient safety, and the ability of non-fasting measures to capture early metabolic dysfunction and real-world glycaemic exposure. This article reviews evidence supporting the prognostic value of postprandial hyperglycaemia and the expanding role of non-fasting monitoring tools. Non-fasting glucose testing offers substantial advantages in terms of accessibility, safety, and clinical relevance, and is well-suited for population screening and routine diabetes monitoring. Fasting glucose testing remains essential for specific diagnostic and research applications, particularly when strict metabolic standardisation is required. A context-driven framework that prioritises non-fasting approaches while reserving fasting tests for targeted indications provides a balanced and patient-centred strategy for contemporary diabetes care.

Diabetes screening↗

PubMed1992

P-31 MR spectrum and histologic changes after intrahepatic arterial injection of iodized oil in normal and cirrhotic rat liver.

Injection of iodized oil (Lipiodol) into the hepatic artery is widely used in the diagnosis and treatment of hepatocellular carcinoma. However, no reports have yet appeared concerning temporal changes in hepatic metabolism following Lipiodol injection. In the present study, Lipiodol was injected into the hepatic arteries of normal and cirrhotic rats, successive P-31 MR measurements were performed, and temporal changes in metabolism were compared with histologic findings. Both normal and cirrhotic rats displayed minimum levels of beta-ATP/PME and beta-ATP/Pi 5 days after hepatic arterial injection of Lipiodol. However, 10 days after injection these values had reverted to the preinjection levels. The metabolic dysfunction observed in the liver following hepatic arterial injection of 0.3 ml/kg b.w. Lipiodol was transient. Moreover, no distinct differences were observed between P-31 MR changes in normal and cirrhotic rats. Conversely, histologic impairment assessed on the basis of hepatic necrosis ratios was most severe 2 days after hepatic arterial injection in both normal and cirrhotic rats, and this did not coincide with the time of the most pronounced metabolic impairment as inferred from P-31 MR changes.

Animals↗

PubMed1993

Glucose sensitivity of ATP-sensitive K+ channels is impaired in beta-cells of the GK rat. A new genetic model of NIDDM.

In the Goto-Kakizaki rat, a new genetic model of NIDDM, insulin response to glucose is selectively impaired. To elucidate the mechanism of this abnormality, we studied the properties of ATP-sensitive K+ channels, the inhibition of which is a key step of insulin secretion induced by fuel substrates, using the patch-clamp technique. The glucose-sensitivity of KATP channels was considerably reduced in GK rats. However, the inhibitory effects of ATP on channel activity and unitary conductance were not significantly different between control and GK rats. Thus, it appears that the impaired insulinotropic action of glucose in beta-cells of GK rats is attributable to insufficient closure of the KATP channels, probably because of deficient ATP production by impaired glucose metabolism. KATP-channel activities in both control and diabetic beta-cells were found to be equally suppressed by glyceraldehyde and 2-ketoisocaproate. These results strongly suggest that the step responsible for the metabolic dysfunction of diabetic beta-cells is located within the glycolytic pathway before glyceraldehyde-3-phosphate or in the glycerol phosphate shuttle.

Adenosine Triphosphate↗

PubMed1997

Cellular and molecular aspects of bladder hypertrophy.

Bladder dysfunction secondary to benign prostatic hyperplasia (BPH) is a major affliction associated with ageing. As the disease slowly progresses, the bladder changes from a state of compensation to decompensation, in which there are severe, irreversible alterations in bladder function. Using a rabbit model of partial outlet obstruction we have identified three major cellular changes in the bladder which result from such obstruction. These include progressive denervation, mitochondrial dysfunction and disturbances of calcium storage and release from the sarcoplasmic reticulum. Our hypothesis is that outlet obstruction results in bladder hypertrophy which induces ischaemia. This leads to a release of intracellular calcium, leading to activation of specific enzymes and generation of free radicals. These then attack the membranes of nerves, sarcoplasmic reticulum and mitochondria. We have demonstrated that pretreatment of rabbits with Pygeum africanum extract (Tadenan) significantly reduced the severity of both the contractile and metabolic dysfunctions induced by partial outlet obstruction. Our current hypothesis is that Tadenan may either prevent the activation of degradative enzymes (or generation of free radicals), or protect the intracellular membranes against the destructive effects of free radicals or degredative enzymes. In conclusion, identifying cellular mechanisms responsible for bladder dysfunction induced by partial outlet obstruction provides new possibilities for non-surgical treatment of BPH. Our studies on Tadenan support this concept that the bladder provides a novel target for therapeutic intervention.

Aging↗

PubMed2001

Role of mitochondrial dysfunction and dopamine-dependent oxidative stress in amphetamine-induced toxicity.

To define the molecular mechanisms underlying amphetamine (AMPH) neurotoxicity, primary cultures of dopaminergic neurons were examined for drug-induced changes in dopamine (DA) distribution, oxidative stress, protein damage, and cell death. As in earlier studies, AMPH rapidly redistributed vesicular DA to the cytoplasm, where it underwent outward transport through the DA transporter. DA was concurrently oxidized to produce a threefold increase in free radicals, as measured by the redox-sensitive dye dihydroethidium. Intracellular DA depletion using the DA synthesis inhibitor alpha-methyl-p-tyrosine or the vesicular monoamine transport blocker reserpine prevented drug-induced free radical formation. Despite these AMPH-induced changes, neither protein oxidation nor cell death was observed until 1 and 4 days, respectively. AMPH also induced an early burst of free radicals in a CNS-derived dopaminergic cell line. However, AMPH-mediated attenuation of ATP production and mitochondrial function was not observed in these cells until 48 to 72 hours. Thus, neither metabolic dysfunction nor loss of viability was a direct consequence of AMPH neurotoxicity. In contrast, when primary cultures of dopaminergic neurons were exposed to AMPH in the presence of subtoxic doses of the mitochondrial complex I inhibitor rotenone, cell death was dramatically increased, mimicking the effects of a known parkinsonism-inducing toxin. Thus, metabolic stress may predispose dopaminergic neurons to injury by free radical-promoting insults such as AMPH.

Amphetamine↗

PubMed1999

Etiology, neurologic correlations, and prognosis in alpha coma.

OBJECTIVE: To determine the factors affecting prognosis in alpha coma (AC). METHODS: Retrospective review of 36 study patients, 36 control coma patients matched for age and etiology, and meta-analysis of 335 cases in the world literature. RESULTS: Principal causes were cardiorespiratory arrest (CRA) (21 patients); infection, metabolic dysfunction, head trauma (3 each); and drugs, stroke and hypoxia (2 each). Outcome was predicated by EEG reactivity to noxious stimuli. Fourteen of the 15 patients with reactive EEGs, had measurable outcome, 8 awoke - all but two had etiologies other than CRA. Fourteen of 19 patients without EEG reactivity died; two had support discontinued and 3 awoke. Following CRA, 16/21 patients died and 3 had support discontinued. Only 3 patients made a good recovery - all with toxic or metabolic etiologies. Literature meta-analysis of 335 cases showed that overall, AC carried a poor prognosis (76% died). CRA (226 cases) had an 88% mortality; strokes (29 cases), a 90% mortality; hypoxia without cardiac arrest (28 cases), a 61% mortality; drug-induced AC (25 cases), an 8% mortality. CONCLUSIONS: Although the cause of AC largely predicts outcome, EEG reactivity in AC predicted survival: most patients with reactivity awoke; most of those without, died. Few survivors had meaningful recovery.

Adult↗

PubMed1985

Reduced hepatic clearance of propranolol induced by chronic carbon tetrachloride treatment in rats.

Effect of liver injury induced by chronic treatment with carbon tetrachloride for 1 to 4 months on hepatic clearance of propranolol was investigated in male Wistar rats. Plasma propranolol level after i.v. and p.o. dosing (1.0 mg/kg) was always higher in the rats which were treated for 2 and 4 months than in control (sham-injected) rats. The chronic treatment reduced hepatic clearance of propranolol significantly, yielding only approximately 30 to 50% of the control clearance value. Distribution volume of this drug was also significantly reduced by the chronic treatment but seemed to be less sensitive to the treatment than the hepatic clearance. Accordingly, the elimination rate constant was decreased slightly in the rats treated longer than 2 months. The chronic treatment for 2 and 4 months also reduced intrinsic hepatic clearance substantially. The hepatic clearance estimated for both these control and chronically treated rats was significantly dependent on the liver blood flow. Furthermore, propranolol was eliminated much more slowly in the injured liver of the rat which was treated for 2 or 4 months than in the control liver when perfused in in vitro technique. It is, therefore, suggested that the metabolic dysfunction induced by chronic treatment with carbon tetrachloride may be directly related to substantial changes in anatomical arrangement of the hepatic circulation (portasystemic shunting), which may be due to a fibrosis of the tissue.

Animals↗

PubMed2005

HIV-1 transactivator of transcription protein induces mitochondrial hyperpolarization and synaptic stress leading to apoptosis.

Despite the efficacy of highly active antiretroviral therapy in reducing viral burden, neurologic disease associated with HIV-1 infection of the CNS has not decreased in prevalence. HIV-1 does not induce disease by direct infection of neurons, although extensive data suggest that intra-CNS viral burden correlates with both the severity of virally induced neurologic disease, and with the generation of neurotoxic metabolites. Many of these molecules are capable of inducing neuronal apoptosis in vitro, but neuronal apoptosis in vivo does not correlate with CNS dysfunction, thus prompting us to investigate cellular and synaptic events occurring before cell death that may contribute to HIV-1-associated neurologic disease. We now report that the HIV-1 regulatory protein transactivator of transcription protein (Tat) increased oxidative stress, ATP levels, and mitochondrial membrane potential in primary rodent cortical neurons. Additionally, a proinflammatory cellular metabolite up-regulated by Tat, platelet-activating factor, also induced oxidative stress and mitochondrial hyperpolarization in neurons, suggesting that this type of metabolic dysfunction may occur on a chronic basis during HIV-1 infection of the CNS. Tat-induced mitochondrial hyperpolarization could be blocked with a low dose of the protonophore FCCP, or the mitochondrial KATP channel antagonist, tolbutamide. Importantly, blocking the mitochondrial hyperpolarization attenuated Tat-induced neuronal apoptosis, suggesting that increased mitochondrial membrane potential may be a causal event in precipitating neuronal apoptosis in cell culture. Finally, Tat and platelet-activating factor also increased neuronal vesicular release, which may be related to increased mitochondrial bioenergetics and serve as a biomarker for early damage to neurons.

Adenosine Triphosphate↗

PubMed1994

AICA riboside improves myocardial ischemia in coronary microembolization in dogs.

This study was undertaken to examine whether 5-amino-4-imidazolecarboxamide (AICA) riboside (acadesine), which augments adenosine release in ischemic myocardium, further attenuates ischemic injury after acute coronary microembolization. The left anterior descending coronary artery was cannulated and perfused with blood from the left carotid artery in 46 dogs, and coronary blood flow (CBF) of the perfused area was measured. In 12 dogs, 15-microns microspheres (5.0 x 10(4)/ml) were injected repeatedly until CBF approached zero. Changes in CBF, fractional shortening, lactate extraction ratio, and adenosine release were measured with and without administration of AICA riboside. In the control group (n = 7), CBF increased to 154 +/- 11 ml.100 g-1.min-1 at 16-30% of total coronary embolization, and adenosine release was 6.1 +/- 1.0 nmol.100 g-1.min-1. Administration of AICA riboside (n = 5) enhanced coronary hyperemia (187 +/- 8 ml.100 g-1.min-1, P < 0.05), adenosine release (11.9 +/- 0.9 nmol.100 g-1.min-1, P < 0.001), and myocardial adenosine content (0.434 +/- 0.069 vs. 0.118 +/- 0.019 nmol/mg wet wt, P < 0.01) and attenuated decreases in fractional shortening and lactate extraction ratio. AICA riboside preserved myocardial tissue ATP content of the embolized area. The administrations of 8-phenyltheophylline (n = 12) and alpha,beta-methyleneadenosine 5'-diphosphate (n = 10) abolished the beneficial effects of AICA riboside. Furthermore, AICA riboside increased ectosolic and cytosolic 5'-nucleotidase activity of the embolized myocardium (n = 12). Thus we conclude that AICA riboside attenuates contractile and metabolic dysfunction by enhancing adenosine release via activation of ectosolic 5'-nucleotidase and inducing local hyperemia in acute coronary microembolization.

5'-Nucleotidase↗

PubMed1986

Influence of space flight on red blood cells.

Losses of red blood cell mass (RCM) averaging 10-15% have been observed consistently in astronauts after space flight; postflight recovery of RCM requires 4-6 wk. Although apparently not harmful to the health and effectiveness of crews during uncomplicated flights, decreased RCM could compromise health and performance in the event of illness, injury, or partial malfunction of the life support system. Whether the loss of RCM would worsen or stabilize in missions longer than 7 months is unknown. As a biological response, it is a significant, predictable reaction whose etiology, biological mechanisms, and potential operational significance are inadequately defined. Weightlessness is probably the primary cause; however, contributory factors may include hypokinesia/hypodynamia, bone loss, muscle atrophy, altered hemodynamics, stress, and metabolic disturbances. Space medical specialists consider other possible influences such as hypoxia, hypobaria, radiation, toxic contaminants, and launch and reentry accelerations as less likely factors. Because the data base on loss of RCM is insufficient for the National Aeronautics and Space Administration's space medical responsibilities, the Life Sciences Research Office ad hoc Working Group on Space Anemia suggested research approaches ranging form fundamental topics such as utilization of erythropoietin and oxygen in target organs and cell-cell interactions, through possible splenic and vascular dysfunctions, metabolic disturbances, and inhibitors of erythropoiesis, to methodology and models.

Body Weight↗

PubMed2006

Cardiovascular disease risk stratification with stress single-photon emission computed tomography technetium-99m tetrofosmin imaging in patients with the metabolic syndrome and diabetes mellitus.

The metabolic syndrome represents a constellation of risk factors caused by insulin resistance, dyslipidemia, hypertension, and obesity, resulting in elevated coronary disease risk. From a multicenter prospective registry of 7,849 patients, the relation among the metabolic syndrome, diabetes, and risk stratification with stress technetium-99m tetrofosmin single photon-emission computed tomography (SPECT) was evaluated. The percentage of stress myocardial defects was calculated as < or = 5%, 5.1% to 10%, 10.1% to 15%, and > 15%. A Cox proportional-hazards model was used to estimate cardiovascular death or myocardial infarction (n = 752). Of 7,849 patients, 42% had the metabolic syndrome. Patients with the metabolic syndrome had an 84% 2-year event-free survival rate, lower than patients with normal metabolic status (p <0.0001). In patients with the metabolic syndrome, the percentage of moderate to severely abnormal SPECT findings ranged from 11% to 44% for those with 3 to 5 risk factors for the metabolic syndrome. There was an additive relation between the number of risk factors for the metabolic syndrome and the extent and severity of abnormalities in SPECT findings (p <0.0001). Patients with 5 risk factors for the metabolic syndrome were at the greatest risk, with hazard ratios from 7.8- to 14.1-fold for mild to severely abnormal SPECT findings. For diabetic patients requiring combined oral and insulin therapy, relative risk ratios increased from 15 to 21.4 for patients with > 5% to > 15% stress myocardial perfusion defects. In conclusion, cardiovascular prognosis is affected by the degree of metabolic dysfunction, and stress-induced reductions in myocardial perfusion provide an accurate means for near-term risk stratification.

Aged↗

PubMed2001

Clinical, biochemical and genetic aspects and neuronal migration in peroxisome biogenesis disorders.

Peroxisome biogenesis disorders (PBDs) are severe autosomal recessive neurological diseases caused by a defect of peroxisomal assembly factors. Zellweger syndrome, the most severe phenotype, is characterized by hypotonia, psychomotor retardation and neuronal migration disorder. Neonatal adrenoleukodystrophy and infantile Refsum disease are milder phenotypes of this disease. Thirteen complementation groups have been established since the genetic heterogeneity of PBDs was elucidated in 1988. Eleven genes for PBDs have been identified either by a functional complementation cloning or by EST homology searches. In 1992, the first gene for PBDs, PEX2, was identified. It encodes peroxisomal integral membrane protein with a RING finger domain. PEX5 and PEX7 are the genes for peroxisomal targeting signal (PTS)-1 and -2 receptors, respectively. PEX3, PEX16 and PEX19 are considered to be required for the early stage of peroxisome biogenesis. PEX13 protein has an SH3 docking site that binds to the PTS-1 receptor. PEX1 and PEX6 encode ABC protein, and PEX10 and PEX12 also encode integral membrane protein, with RING finger. Temperature-sensitivity, whereby peroxisomal biogenesis and metabolic dysfunctions are restored at 30 degrees C in cells from mild phenotypes, is a useful event for predicting the clinical severity and for elucidation of peroxisome biogenesis. Investigations using knockout mice are expected to facilitate understanding of migration disorders.

Animals↗

PubMed1999

Sulphation deficit in "low-functioning" autistic children: a pilot study.

BACKGROUND: Parents of autistic children and autism support groups often report that autistic episodes are exacerbated when the children eat certain foodstuffs such as dairy products, chocolates, wheat, corn sugar, apples, and bananas. The hypothesis that autistic behavior might be related to metabolic dysfunctions has led us to investigate in a group of "low functioning" autistic children and in an age-matched control group each made up of 20 subjects, the sulphation capacity available. METHODS: Utilizing the biochemical characteristics of paracetamol we evaluated by high performance liquid chromatography, the urine paracetamol-sulfate/paracetamol-glucuronide (PS/PG) ratio in all subjects following administration of this drug. RESULTS: The PS/PG ratio in the group of autistic subjects gave a significantly lower results than the control group with p < .00002. CONCLUSIONS: The inability to effectively metabolize certain compounds particularly phenolic amines, toxic for the CNS, could exacerbate the wide spectrum of autistic behavior.

Acetaminophen↗

PubMed2006

Vitamins C and E protect hepatic cytochrome P450 dysfunction induced by polymicrobial sepsis.

The effect of vitamins C and E on the activity and gene expression of hepatic microsomal cytochrome P450 (CYP) during polymicrobial sepsis was studied. The serum aminotransferase and lipid peroxidation levels increased 24 h after the cecal ligation and puncture, and this increase was attenuated by vitamins C and E. The hepatic concentrations of the reduced glutathione decreased in the septic animals, which was inhibited by vitamin C. Both the activities and mRNA expression of CYP1A1 and CYP2E1 decreased after cecal ligation and puncture, which was prevented by vitamins C and E. The decrease in CYP1A2 activity in the liver from cecal ligation and puncture was prevented by vitamins C and E. Our findings suggest that vitamins C and E improve hepatic drug metabolizing dysfunction as indicated by abnormalities in CYP isoforms during sepsis, and this protection is, in major part, caused by decreased oxidant stress and lipid peroxidation.

Animals↗

PubMed2005

Monosodium glutamate in standard and high-fiber diets: metabolic syndrome and oxidative stress in rats.

OBJECTIVE: This study determined the effects of adding monosodium glutamate (MSG) to a standard diet and a fiber-enriched diet on glucose metabolism, lipid profile, and oxidative stress in rats. METHODS: Male Wistar rats (65 +/- 5 g, n = 8) were fed a standard diet (control), a standard diet supplemented with 100 g of MSG per kilogram of rat body weight, a diet rich in fiber, or a diet rich in fiber supplemented with 100 g of MSG per kilogram of body weight. After 45 d of treatment, sera were analyzed for concentrations of insulin, leptin, glucose, triacylglycerol, lipid hydroperoxide, and total antioxidant substances. A homeostasis model assessment index was estimated to characterize insulin resistance. RESULTS: Voluntary food intake was higher and feed efficiency was lower in animals fed the standard diet supplemented with MSG than in those fed the control, fiber-enriched, or fiber- and MSG-enriched diet. The MSG group had metabolic dysfunction characterized by increased levels of glucose, triacylglycerol, insulin, leptin, and homeostasis model assessment index. The adverse effects of MSG were related to an imbalance between the oxidant and antioxidant systems. The MSG group had increased levels of lipid hydroperoxide and decreased levels of total antioxidant substances. Levels of triacylglycerol and lipid hydroperoxide were decreased in rats fed the fiber-enriched and fiber- and MSG-enriched diets, whereas levels of total antioxidant substances were increased in these animals. CONCLUSIONS: MSG added to a standard diet increased food intake. Overfeeding induced metabolic disorders associated with oxidative stress in the absence of obesity. The fiber-enriched diet prevented changes in glucose, insulin, leptin, and triacylglycerol levels that were seen in the MSG group. Because the deleterious effects of MSG, i.e., induced overfeeding, were not seen in the animals fed the fiber-enriched diets, it can be concluded that fiber supplementation is beneficial by discouraging overfeeding and improving oxidative stress that is induced by an MSG diet.

Animals↗