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PubMed1995

[Physiologic, biochemical and genetic aspects of malignant hyperthermia].

Malignant hyperthermic syndrome (MHS) is based on a metabolic dysfunction of the skeletal muscle. It is characterized by an elevation of muscle metabolism and rigidity, accompanied by an increase of arterial pCO2, lactate and potassium plasma concentration, and body temperature. In sensitive individuals, MHS can be evoked pharmacologically. To identify substances that evoke this syndrome or those useful for its therapy, MHS is modelled in pigs. The primary defect attributed to MHS is the impairment of sarcoplasmic calcium homeostasis based on a dysfunction of one of calcium ion channels. In some cases, genetic mapping has shown that MHS is related to changes in 19 chromosome (in humans). Abnormal function of the ion channel is probably not sufficient for the expression of MHS. The syndrome manifests only when several modifying factors coincide.

Animals↗

PubMed1995

[Physiologic, biochemical and genetic aspects of malignant hyperthermia].

Animals↗

PubMedDate not supplied

Intestinal mucosal enzymes in the diagnosis of gastrointestinal metabolic disease.

The small intestinal mucosa is an actively metabolizing, rapidly proliferating, absorptive epithelium with nutritional and homeostatic functions. A metabolic dysfunction of this organ might, therefore, be expected to cause not only gastrointestinal dysfunction, but also systemic symptoms. Several diseases characterized by primary or secondary gastrointestinal metabolic alterations are discussed.

Acrodermatitis↗

PubMed1991

Characterization of an endotoxemic baboon model of metabolic and organ dysfunction.

An anesthetized endotoxemic baboon model has been developed by infusing 2.0 mg E. coli endotoxin/kg i.v. over 1 hr (n = 7). Animals were monitored for 5-7 days with analyses of: cardiovascular, metabolic, and organ dysfunction; acid base, hemostatic, and hematological alterations; as well as tumor necrosis factor (TNF) and interleukin-6 (IL-6) levels. Pathophysiologies detected at 2 hr included transient decreases in vascular resistance and blood pressure, a 157% increase in blood lactate, and a 90% decrease in circulating neutrophils. Organ dysfunction was not observed until 24 hr and, although thrombocytopenia was prevalent (-72% at 48 hr), disseminated intravascular coagulation (DIC) was not a major pathology. Hematocrit fell 21% by 24 hr and was -41% at 5-7 days. Serum TNF peaked at 90 min (7.8 +/- 0.2 ng/mL) and was undetectable after 3 hr. IL-6 also increased early, peaked at 3 hr (3872 +/- 846 U/mL) and was still detectable at 24 hr. A low mortality primate model of gram-negative sepsis has been developed that is characterized by early cardiovascular and metabolic dysfunction (2-6 hr), late organ dysfunction (24-48 hr), sub-clinical DIC, a prolonged anemia, and a 29% mortality between 48 and 72 hr.

Acid-Base Equilibrium↗

PubMed1998

Pharmacotherapy for traumatic brain injury: a review.

Traumatic brain injury in the United States is a serious health problem: it is a significant factor in approximately half of all trauma-related deaths, and, leads to persistent, long-term neurologic dysfunction in survivors. Physiological changes that accompany brain trauma such as cardiovascular alterations, hypercapnia, hypoxiaischemia, metabolic dysfunction, and alterations in the endogenous neurochemical systems are associated with poor clinical outcome. Using a variety of animal models, experimental studies have begun to elucidate these neurochemical disturbances that underlie the behavioral deficits and the pathologic outcome. Modification of the post-traumatic neurochemical milieu can promote functional recovery. While a number of currently available pharmaceutical compounds have been reported to be effective in various animal models of TBI, their utility in the clinical setting has been disappointing [119]. New hope has arisen for the treatment of TBI, based upon new research findings regarding the development of novel pharmacological therapies for brain trauma. Reduction of brain temperature can maintain relative tissue homeostasis by lowering metabolic activity. Hypothermia has been attempted in patients over the past 50 years and recent experimental evidence suggests that posttraumatic hypothermia can attenuate EAA release and free-radical production [120]. In animal models, hypothermic treatment has attenuated post-traumatic neurologic motor dysfunction [121,122], improved histopathologic damage [123,124], and reduced the extent of cytoskeletal damage [120]. In addition, the armamentarium of potentially neuroprotective compounds, which has increased rapidly in the recent years, provides promising pharmacological therapies for the treatment of TBI.

Animals↗

PubMed1990

Growth of Bacillus stearothermophilus on glycerol in chemostat culture: expression of an unusual phenotype.

Bacillus stearothermophilus grew readily on glycerol in carbon-limited chemostat culture and expressed a high carbon conversion efficiency. However, the strain of organism used (probably B. stearothermophilus var. nondiastaticus) proved particularly sensitive to glycerol, both respiration and growth being severely impeded by any surfeit of this compound. Sensitivity was found to correlate with an exceptionally high level of expression of glycerol kinase [activities of more than 80 mumol min-1 (mg protein)-1 were manifest in crude cell-free extracts], coupled with low activities of methylglyoxal synthase and of glyoxylase (enzymes of the methylglyoxal bypass). It is proposed that metabolic dysfunction results from an uncontrolled gross accumulation of glycerol phosphate (and early products of its metabolism) within the cells, coupled with depletion of the intracellular phosphate pool.

Carbon Dioxide↗

PubMed1996

Skeletal muscle metabolism as a target for drug therapy in peripheral arterial disease.

Peripheral arterial disease (PAD) is an atherosclerotic disease which modifies lower extremity hemodynamics. There is considerable evidence that skeletal muscle metabolism is altered in PAD. Several studies have demonstrated altered mitochondrial enzyme content in PAD muscle as compared with controls, and enzyme activity may not increase normally in PAD with exercise training. A variety of metabolic intermediates, including acylcarnitines, accumulate in muscle of PAD patients, suggesting incomplete oxidative metabolism. Studies employing 31P-NMR (nuclear magnetic resonance) also suggest a metabolic myopathy in PAD. Strikingly, while hemodynamics do not predict claudication-limited performance, metabolic injury as evidenced by acylcarnitine accumulation is strongly correlated with patients' functional status in PAD. Further, exercise rehabilitation improves claudication-limited performance without modifying large vessel hemodynamics. The stress placed on skeletal muscle during exercise in PAD and the observed evidence of metabolic dysfunction is similar to ischemia/reperfusion injury in cardiac muscle. Recognition of the role of cellular metabolic injury and function in PAD has formed the basis for novel therapeutic strategies in this disease.

Adenosine Triphosphate↗

PubMed1992

PET correlates of normal and impaired memory functions.

To date, positron emission tomography (PET) has been the only technology for the quantitative imaging of the changes of regional cerebral glucose (rCMRGl) or oxygen metabolism and blood flow (rCBF) associated with psychophysical stimulation and with the performance of mental tasks. So far, the majority of studies performed in healthy subjects demonstrated activation patterns involving not only certain limbic structures, most of all hippocampus, amygdala, parahippocampus, and cingulate, but also temporal, parietal, and occipital association cortex, depending on the applied paradigm. Indeed, the closest correlation between regional metabolism and memory test scores was found in mesiotemporal structures during the performance of memory tasks. Metabolic or CBF studies also seem to indicate that memorizing strategies may differ among individuals. PET was repeatedly used to investigate metabolic and/or blood flow abnormalities in patients with various amnestic syndromes. In cases with uni- or bilateral lesions of mesiotemporal structures, caused by surgery, herpes simplex encephalitis, or permanent ischemic, anoxic, or toxic damage, disturbances of metabolism and blood flow typically extended far beyond the morphological defects detected by computed tomography or magnetic resonance. In acute transient global amnesia, CBF and metabolism were decreased bilaterally in the mesiotemporal lobes, where hypometabolism persisted for some time, while higher values were observed in thalamus and some cortical areas. Diencephalic lesions causing Korsakoff's syndrome were associated with decreased rCMRGl in the hippocampal formation, upper brainstem, cingulate, and thalamus. Discrete thalamic infarcts caused amnesia and metabolic depression in the morphologically intact ipsilateral thalamus and in various projection areas of the infarcted nuclei. In ischemic forebrain lesions, amnestic deficits could be related to involvement of the anterior cingulate and of basal cholinergic nuclei. A large number of pathologies are diffusely spread out in the brain and affect partially or predominantly structures in memory processing. This holds true especially in the various dementias where memory disturbances are a consistent and often leading feature. Notably, Alzheimer's disease can be distinguished from other dementias by its characteristic pattern of metabolic dysfunction, with the most prominent changes occurring in parietotemporal and frontal association cortex whose residual metabolism is related to the severity of the disease. Therefore, activation studies using paradigms involving memory functions enhance that typical pattern. Only in the activated state is metabolism of mesiotemporal structures significantly correlated with the performance in memory tests. Other dementias also affect some of the distributed memory networks, with Huntington's disease suggesting a role of the striatum in memory processing.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1998

Costello syndrome: phenotype, natural history, differential diagnosis, and possible cause.

We describe 8 patients affected with Costello syndrome including an affected sib pair and review the literature on 29 previously reported cases. We emphasize an association with advanced parental age, which is consistent with autosomal dominant inheritance with germline mosaicism. The pathogenesis appears to involve metabolic dysfunction, with growth disturbance, storage disorder appearance, acanthosis nigricans, hypertrophic cardiomyopathy, and occasional abnormalities of glucose metabolism. Although the cause is currently unknown, Costello syndrome is interesting because of a potential genetic-metabolic etiology.

Acanthosis Nigricans↗

PubMed2002

Advances in polycystic ovary syndrome treatment: metformin and ovarian diathermy.

Polycystic ovary syndrome (PCOS) affects approximately 6% of women in their reproductive years. The symptoms of the syndrome are chronic anovulation and androgen excess. Infertility due to ovulatory dysfunction is a common problem for women with PCOS. Metformin, an antihyperglycemic agent, can correct the metabolic dysfunction that occurs with PCOS, and also stimulate folliculogenesis. The drug is effective alone and in combination with clomiphene citrate. An alternative option, ovarian diathermy, also promotes ovulation through changes in the intraovarian hormonal environment. Both techniques provide promising and effective alternatives for women with PCOS who do not respond to traditional oral ovulation induction agents.

Algorithms↗

PubMed2001

Targeting ceramide metabolism--a strategy for overcoming drug resistance.

Inherent or acquired drug resistance, which frequently characterizes cancer cells, is caused by multiple mechanisms, including dysfunctional metabolism of the lipid second messenger ceramide. Ceramide, the basic structural unit of the sphingolipids, plays a role in activating cell death signals initiated by cytokines, chemotherapeutic agents, and ionizing radiation. Recent discoveries about the metabolism of ceramide suggest that this agent may have an important influence on the effectiveness of various cancer therapeutics. In particular, the cytotoxic effect of chemotherapy is decreased when generation of ceramide is impaired but is increased when the degradation of ceramide is blocked. Herein, we review the mechanisms of resistance to chemotherapeutic agents in terms of ceramide metabolism.

Animals↗

PubMed2026

Feeding the epigenome: EZH2 as a metabolic integrator of cell fate in development and cancer.

Epigenetic regulation is intimately linked to cellular metabolism, enabling environmental and nutritional cues to shape gene expression programs through dynamic modifications of chromatin structure. This metabolism-epigenetics interface is mediated, in part, by the dependence of chromatin-modifying enzymes on key metabolites, including S-adenosylmethionine (SAM), acetyl-CoA, UDP-GlcNAc, and α-ketoglutarate, which serve as substrates or cofactors for DNA and histone modifications. Among these regulators, EZH2, the catalytic subunit of Polycomb Repressive Complex 2 (PRC2), has emerged as a key mediator linking metabolic state to epigenetic regulation by translating metabolic inputs into changes in chromatin architecture and gene expression. EZH2 governs developmental cell fate through H3K27me3-mediated gene repression and is frequently dysregulated in cancer, where it promotes dedifferentiation, tumor progression, and metabolic reprogramming. Importantly, EZH2 activity is itself modulated by cellular metabolic status through posttranslational modifications, including phosphorylation, acetylation, methylation, ubiquitination, and O-GlcNAcylation, which influence its stability, catalytic activity, and chromatin-binding capacity. These modifications are responsive to nutrient availability and signaling pathways involving glucose, SAM, NAD+, and other metabolic intermediates. Consequently, disruption of this finely tuned regulatory network can contribute to developmental abnormalities, metabolic dysfunction, and oncogenesis. In this review, we examine the molecular mechanisms governing EZH2 regulation and discuss how metabolic control of EZH2 shapes chromatin dynamics, cell fate decisions, and disease pathogenesis. Elucidating how metabolic signals modulate EZH2 activity will advance our understanding of development and disease while uncovering potential therapeutic opportunities to target metabolism-driven epigenetic dysregulation.

Humans↗

PubMed2000

Metabolic and cognitive response to human traumatic brain injury: a quantitative proton magnetic resonance study.

Proton magnetic resonance spectroscopy (1H-MRS) offers a unique insight into brain cellular metabolism following traumatic brain injury (TBI). The aim of the present study was to assess change in neurometabolite markers of brain injury during the recovery period following TBI. We studied 19 TBI patients at 1.5, 3, and 6 months postinjury and 28 controls. We used 1H-MRS to quantify N-acetylaspartate (NAA), creatine (Cre), choline (Cho), and myoinositol (mIns) in occipitoparietal gray matter (GM) and white matter (WM) remote from the primary injury focus. Neuropsychological testing quantified cognitive impairment and recovery. At 1.5 months, we found cognitive impairment (mean z score = -1.36 vs. 0.18,p < 0.01), lower NAA (GM: 12.42 mM vs. 13.03, p = 0.01; WM: 11.75 vs. 12.81, p < 0.01), and elevated Cho (GM: 1.51 vs. 1.25, p < 0.01; WM: 1.98 vs. 1.79, p < 0.01) in TBI patients compared with controls. GM NAA at 1.5 months predicted cognitive function at outcome (6 months postinjury; r = 0.63, p = 0.04). GM NAA continued to fall by 0.46 mM between 1.5 and 3 months (p = 0.02) indicating continuing neuronal loss, metabolic dysfunction, or both. Between 3 and 6 months, WM NAA increased by 0.55 mM (p = 0.06) suggesting metabolic recovery. Patients with poorer outcomes had elevated mean GM Cho at 3 months postinjury, suggesting active inflammation, as compared to patients with better outcomes (p = 0.002). 1H-MRS offers a noninvasive approach to assessing neuronal injury and inflammation following TBI, and may provide unique data for patient management and assessment of therapeutic efficacy.

Adolescent↗

PubMedDate not supplied

Double-blind, crossover, placebo-controlled clinical trial with L-acetylcarnitine in patients with degenerative cerebellar ataxia.

Despite the different genetic defects underlying degenerative ataxias, it has been suggested that mitochondrial energy production and antioxidative metabolism dysfunction may be common biochemical alterations related to these diseases. Acetylcarnitine, a cholinomimetic substance, is involved in oxidative metabolism and is a potential source of acetyl groups for the synthesis of acetylcholine in the mammalian brain. To determine whether treatment with L-acetylcarnitine may improve some clinical conditions of patients with ataxia, a double-blind crossover study with L-acetylcarnitine was performed in 24 patients with degenerative cerebellar diseases. Patients were selected from an ongoing prospective follow-up study at the Department of Neurology at the University of Florence, Italy. Each treatment phase with L-acetylcarnitine or placebo lasted 6 months, after which patients were crossed over to the other treatment phase. Ataxia was documented and quantified with use of a clinical score. After the trial, we observed a statistically significant improvement of some symptoms and a slow progression of the disease in both groups of patients.

Acetylcarnitine↗

PubMed1990

Improvement of hypoperfusion with norepinephrine injury by ex vivo insulin in isolated diabetic rat hearts.

Effects of insulin on contractile and energy metabolic dysfunctions during hypoperfusion (2 ml/min/g heart wt., 60 min) with 10(-6) M norepinephrine were studied in paced hearts isolated from streptozotocin-diabetic rats. Insulin (2 mU/min/g heart wt.) was infused 20 min before and during hypoperfusion (pre-treated group) or 30 min after the onset of hypoperfusion (post-treated group). Hearts in the non-treated group were hypoperfused without insulin and other hearts in the control group were not hypoperfused. In the non-treated group, resting contractile force (CF) and resting left ventricular pressure (LVP) were significantly elevated to maximum levels within 30 min after hypoperfusion and these elevations were restored in the pre-treated group but not in the post-treated group. Developed CF was depressed in the non-treated group and improved significantly in the pretreated group but not in the post-treated group. Developed LVP was depressed in the non-treated group, and depression was slightly larger in the pre-treated group. In the non-treated group, ATP and creatine phosphate contents in the left ventricle significantly decreased. Decreases in ATP and creatine phosphate contents in the inner layer were partially restored in the pre-treated group but not in the post-treated group. Lactate significantly increased in the non-treated group and increased even further in the insulin treated groups. These results indicate that contractile dysfunction during hypoperfusion with norepinephrine is improved by pre-treated insulin, as is partial recovery of energy metabolism.

Adenosine Triphosphate↗

PubMed2001

Aspirin treatment improves bladder function after outlet obstruction in rabbits.

OBJECTIVES: To examine whether bladder smooth muscle dysfunction after outlet obstruction could be altered by treatment with aspirin. Long-term outlet obstruction causes contractile and metabolic dysfunction of the bladder in vivo and in vitro. The evidence is growing that a decrease in bladder perfusion is an important cause of this phenomenon. The platelet aggregation inhibitor, acetylsalicylic acid (aspirin), has been used to improve perfusion of the heart for decades. METHODS: Ten male New Zealand white rabbits were obstructed for 4 weeks. Five rabbits received no further treatment (Obs), and 5 rabbits received 2 mg/kg/day aspirin (Obs+aspirin), administered by an osmotic pump implanted subcutaneously 1 week before the surgical obstruction. The bleeding time was measured to confirm the effectiveness of the aspirin treatment. Three different control groups were created: sham-operated rabbits, unobstructed rabbits with pumps containing DMSO (vehicle), and unobstructed rabbits with pumps containing aspirin. The contractile responses of bladder strips to field stimulation, adenosine triphosphate, carbachol, and KCl were determined. A section of each detrusor tissue was fixed in formalin and used to determine the smooth muscle and collagen (connective tissue) volume fraction. RESULTS: No differences were found in the bladder weights or responses to stimuli in the different control groups, which were therefore combined. Partial bladder outlet obstruction caused significant increases in the bladder weight of the obstructed animals (Obs+aspirin, 10.15 +/- 0.87 g; Obs, 10.17 +/- 0.88 g; and controls, 2.87 +/- 0.21 g). The aspirin treatment increased the bleeding time from 1.7 +/- 0.3 minutes to 3.3 +/- 0.1 minutes. The responses to field stimulation were significantly reduced in all of the obstructed rabbits. However, the responses of the bladder strips from the Obs rabbits to field stimulation were impaired to a significantly greater degree than were those from the Obs+aspirin rabbits. The response to 32-Hz stimulation was reduced by 86% in the Obs group but by only 64% in the Obs+aspirin group. The responses to carbachol were significantly reduced by 62% in the strips from the Obs rabbits, but the responses of the strips from the Obs+aspirin rabbits were similar to the responses of the strips from the controls. The responses to KCl and adenosine triphosphate were reduced, although they just failed to achieve statistical significance using Bonferroni's analysis. The ratio of smooth muscle and connective tissue shifted slightly toward smooth muscle after 4 weeks of obstruction, but no difference was found with or without aspirin treatment. CONCLUSIONS: Low-dose aspirin has a small but significant protective effect on the contractile dysfunction induced by bladder outlet obstruction in rabbits, although the increase in bladder mass was not altered. Bladders of the same weight showed improved responses to all forms of stimulation after pretreatment with aspirin. Already used by millions of patients with heart diseases, aspirin could be a useful protection against contractile dysfunction of the obstructed bladder.

Animals↗

PubMed1980

Schizophrenia-like psychosis caused by a metabolic disorder.

Four patients with an intermittent psychosis closely resembling hallucinogenic drug-induced states were suspected of having a porphyric disease and were investigated for a possible relation between the metabolic dysfunctions of porphyria and the psychotic syndrome. Theoretically the link could be in a disturbance of serine and glycine metabolism. This theory was supported by disturbances in serine and glycine excretion found in all patients during psychotic episodes. In addition, loading with one low oral dose of serine produced psychotic symptoms 5 h later which lasted 3-6 h. One patient reacted to glycine in the same way. These findings suggest that disturbed serine-glycine metabolism may have a key role in certain schizophreniform psychotic syndromes.

Adolescent↗

PubMed2026

Celery seed extract attenuates sarcopenic obesity and age-related sarcopenia by reducing intramuscular lipid accumulation in mice.

BACKGROUND & AIMS: Sarcopenia is characterized by progressive loss of skeletal muscle mass and function and is increasingly recognized to be influenced by metabolic disturbances associated with aging and obesity. Intramuscular lipid accumulation has emerged as a key pathological feature linking metabolic dysfunction to skeletal muscle deterioration. Celery seed extract (CSE) possesses anti-obesity, anti-inflammatory, and antioxidant properties; however, its potential role in skeletal muscle metabolism has not been well investigated. This study aimed to determine whether CSE attenuates skeletal muscle deterioration associated with obesity and aging through modulation of intramuscular lipid accumulation and related metabolic pathways. METHODS: Diet-induced obese mice and naturally aged mice were used to evaluate the effects of CSE supplementation. Skeletal muscle mass, grip strength, muscle morphology, intramuscular lipid content, mitochondrial metabolic signaling, inflammatory responses, and muscle protein turnover pathways were assessed using biochemical, molecular, and histological analyses. RESULTS: CSE supplementation significantly improved skeletal muscle mass, grip strength, and muscle fiber cross-sectional area in both obese and aged mice. These improvements were accompanied by reduced intramuscular triglyceride and cholesterol accumulation. Mechanistically, CSE improved mitochondrial metabolic signaling by activating the AMPK-PGC-1α pathway and increasing mitochondrial oxidative phosphorylation proteins. In addition, CSE suppressed inflammatory signaling pathways, including MAPK activation and NLRP3 inflammasome signaling, and improved muscle proteostasis by enhancing myogenic regulators while reducing the expression of proteolytic factors such as MuRF1, Atrogin-1, and myostatin. Correlation analyses further indicated that intramuscular lipid accumulation was closely associated with mitochondrial dysfunction, inflammatory activation, and muscle atrophy. CONCLUSIONS: These findings demonstrate that CSE alleviates skeletal muscle deterioration in both obesity- and aging-associated sarcopenia by reducing intramuscular lipid accumulation and improving mitochondrial metabolism, inflammatory responses, and muscle protein turnover. Targeting intramuscular lipid accumulation may therefore represent a promising nutritional strategy for preventing sarcopenia associated with metabolic and aging-related stress.

AMPK–PGC-1α↗